Micropipette system

Abstract

To provide a micropipette system with which it is possible for an operator to control suction and discharge of fluid with the same intuitiveness as with operation by a mouthpiece.SOLUTION: A micropipette system according to the present invention includes: a barrel part which has a long axis, a proximal end, and a distal end, and which further has a tubular cavity extending along at least a portion of the long axis; a rotatable wheel having a rotation axis within the proximal-side region of the barrel part; a pump member configured to move forward and rearward in a distal direction or a proximal direction within the barrel part in conjunction with the rotational movement of the wheel; and a microcapillary needle extending so as to protrude from the barrel part in the proximal direction. The outer edge of the wheel is at least partially exposed from the barrel part. The internal space of the microcapillary needle communicates with the tubular cavity of the barrel part. The forward and rearward movement of the pump member increases or reduces the volume of the tubular cavity, thereby enabling suction or discharge of fluid within the internal space of the microcapillary needle.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present disclosure relates to a micropipette system suitable for delicate manipulation of minute particles such as mammalian ova, fertilized eggs, and early embryos. The micropipette system may be used, for example, in assisted human reproduction, livestock breeding techniques, and laboratory animal reproductive engineering. [Background technology]

[0002] For example, in the fields of assisted reproductive technology for humans, breeding technology for livestock such as cows, and reproductive engineering for laboratory animals such as mice, manipulation of eggs, fertilized eggs, and early embryos under a microscope is routinely performed. The manipulations referred to here include fertilizing these samples, separating them from accompanying substances, selecting, moving, transferring, etc. In modern society, assisted reproductive technology, including in vitro fertilization and embryo transfer, is becoming increasingly important. Similarly, in the fields of breeding technology for livestock cattle and reproductive engineering for laboratory animals, in vitro fertilization is widely used and is of high importance. Needless to say, these techniques require rapid manipulation while handling a micro-suspension environment on the order of microliters without damaging delicate embryos, etc. While good manipulation of embryos, etc. depends largely on the skill of the operator, it is important to improve the reliability, safety, and efficiency of manipulation techniques by improving equipment and tools.

[0003] In particular, it is desirable to have an operating instrument that can control the introduction and release of fluid through a microcapillary needle according to the "intuition" of an operator observing a suspension of minute embryos or the like under a microscope, and that can suck up, move, and dispense an appropriate amount of an appropriate part of the suspension at the appropriate time.

[0004] Conventionally, there are two main styles for manipulating eggs, fertilized eggs, and early embryos (hereinafter, these are sometimes collectively referred to as "embryo manipulation"): a mouthpiece style and a micropipette style. In the mouthpiece style, an operator holds a mouthpiece attached to the other end of a tube with a microcapillary needle at the tip in his mouth, and controls the inflow and outflow of a fluid containing cells such as an embryo in the microcapillary needle by the operator's delicate inflow and outflow. The mouthpiece style is highly intuitive. In other words, it is easier than other methods for an operator to inflow and out of the desired amount of fluid at the desired timing. In Japan, the mouthpiece style is the mainstream for embryo manipulation, and the present inventor estimates that the majority of human embryo manipulations, as well as almost all embryo manipulations of livestock such as cows and laboratory animals, are performed using the mouthpiece style.

[0005] However, there are some countries where the use of mouthpiece-type devices is not permitted, for example, in human embryo manipulation, because there is a theoretical possibility that the operator's breath could transmit pathogenic microorganisms, including viruses, to the embryo or other organs, or that the operator who holds the mouthpiece in his / her mouth could be adversely affected by the oral route.

[0006] Patent Document 1 discloses an adjustable pipette. The pipette of Patent Document 1 has a structure in which the body is wrapped around the four fingers and palm as if holding a rod, and the spring-loaded rod protruding in the distal direction is pushed and pulled with the remaining thumb to control the intake and discharge of fluid. Such thumb-controlled micropipettes are usually configured to be adjustable so that the operator can intake and discharge a precise amount of liquid specified in advance before use, and are widely used in modern life science laboratories. Thumb-controlled micropipettes are also used in the field of embryo manipulation, and are sold by CooperSurgical, Inc. under the name of The STRIPPER (registered trademark) (https: / / fertility.coopersurgical.com / micropipettes / the-stripper / #toggle).

[0007] Micropipettes have the advantage of avoiding the above-mentioned potential problems of the mouthpiece type (i.e., the involvement of exhaled air and the use of the mouth during operation). However, many skilled in the art feel that conventional micropipettes are far inferior to mouthpiece types in terms of the ability to intuitively control the injecting and ejecting of fluids. For example, this is thought to be one of the main reasons why the use of micropipettes has not become widespread among skilled in the art of embryo manipulation in Japan, and mouthpiece types continue to be used. In other words, in the field of embryo manipulation in the field of assisted reproductive technology, it is not the ability to accurately aspirate and eject a pre-specified amount of liquid, which is the original purpose of the micropipette as described in Patent Document 1, that is required, but rather the ability to change the amount of liquid (including cells such as embryos) to be aspirated and ejected flexibly and freely during the operation, depending on the number and state of the embryos being handled, according to the operator's intuition, at the level of a single cell.

[0008] There are also electronic micropipettes, which can aspirate and dispense precise amounts of liquid on the microliter scale or below, but are not good at adjusting the amount of liquid fluidly according to the operator's sense. There are also fixed hydraulic or pneumatic micropipettes (microinjectors) used for special purposes such as microinjection, but these devices are expensive and have limited range of operation and applications. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] U.S. Patent No. 3,827,305 Summary of the Invention [Problem to be solved by the invention]

[0010] An embodiment of the present disclosure provides a micropipette system that allows an operator to control the intake and discharge of fluid with an intuitiveness comparable to that of a mouthpiece-type operation. [Means for solving the problem]

[0011] The present disclosure includes the following embodiments. [1] a barrel having a longitudinal axis and proximal and distal ends, the barrel having a tubular cavity extending along at least a portion of the longitudinal axis; a rotatable wheel having an axis of rotation in a proximal region of the torso; a pump member configured to move back and forth in a distal or proximal direction within the body in response to rotational movement of the wheel; a microcapillary needle extending proximally from the barrel; A micropipette system comprising: an outer edge of the wheel is at least partially exposed from the body portion; the microcapillary needle has an internal space communicating with the tubular cavity of the body; the back and forth movement of the pump member increases or decreases the volume of the tubular cavity, thereby allowing the intake or exhaust of fluid in the interior space of the microcapillary needle. Micropipette system. [2] The micropipette system according to [1], wherein the tubular cavity extends distally of the pump member, and the tubular cavity and the internal space of the microcapillary needle are connected by a conduit that makes a U-turn from the distal direction to the proximal direction. [3] The pump member has a piston that fits into the inner diameter of the tubular cavity and is movable back and forth within the tubular cavity, and a linear gear that is connected to the piston and extends to a side opposite the tubular cavity, The micropipette system includes a circular gear that rotates together with the wheel, and the rotation axis of the wheel is fixed to the body; The back and forth movement of the pump member based on a rack and pinion mechanism caused by the engagement between the circular gear and the linear gear provides a link between the rotational movement of the wheel and the back and forth movement of the pump member. The micropipette system according to [1] or [2]. [4] the engagement between the circular gear and the linear gear in the rack-and-pinion mechanism is indirect engagement via one or more additional circular gears engaged between the circular gear and the linear gear; The micropipette system of [3], wherein one of the one or more additional circular gears directly engages with the linear gear rather than the circular gear. [5] The micropipette system of [3] or [4], wherein the circular gear is concentric with the wheel and connected to the wheel, and the diameter of the circular gear is less than or equal to 2 / 3 of the diameter of the wheel. [6] the tubular cavity being provided, at least in part, by a flexible tubing region; a second wheel is coupled to the wheel and rotates concentrically with the wheel, one of the wheel and the second wheel forming a circular gear; the barrel includes a barrel-fixed linear gear extending along the longitudinal axis and fixed to the barrel and engaging the circular gear; When the wheel and the second wheel rotate, the circular gear rolls on the trunk-fixed linear gear, and the wheel and the second wheel move along the trunk-fixed linear gear, The outer edge of the wheel that does not constitute the circular gear out of the wheel and the second wheel is in circumscribing the flexible tube region and compressing a tubular cavity in the flexible tube region, so that the outer edge of the wheel itself constitutes a pump member based on a peristaltic pump mechanism that moves back and forth in conjunction with the rotational movement of the wheel. The micropipette system according to [1] or [2]. [7] The pump member includes a piston that fits into an inner diameter of the tubular cavity and is movable back and forth within the tubular cavity, and a connecting rod that is connected to the piston and extends to a side opposite the tubular cavity, The connecting rod is fixed to a rotation axis of the wheel at an end opposite to the end connected to the piston, the micropipette system includes a circular gear that rotates in unison with the wheel; the barrel includes a barrel-fixed linear gear extending along the longitudinal axis and fixed to the barrel and engaging the circular gear; When the wheel rotates, the circular gear rolls on the linear gear fixed to the body, and the wheel moves along the linear gear fixed to the body; The movement of the wheel along the body fixed linear gear also moves the pump member via the connecting rod, thereby providing a link between the rotational movement of the wheel and the back and forth movement of the pump member. The micropipette system according to [1] or [2]. [8] the pump member has a piston that fits into an inner diameter of the tubular cavity and is movable back and forth within the tubular cavity, the piston having a connecting rod fixed thereto and extending to a side opposite the tubular cavity; The rotation axis of the wheel is fixed to the body, the connecting rod is fixed at an end opposite to the end fixed to the piston to a position on the wheel offset from the rotation axis; A slider-crank mechanism formed by connecting the wheel and the piston with the connecting rod provides a link between the rotational movement of the wheel and the back-and-forth movement of the pump member. The micropipette system according to [1] or [2]. [9] [8] The micropipette system according to the present invention, the micropipette system includes a circular gear that rotates in unison with the wheel, and one or more additional circular gears that engage with the circular gear; the connecting rod is fixed at an end opposite to the end fixed to the piston at a position offset from the axis of rotation of one of the one or more additional circular gears rather than the wheel; A micropipette system, wherein a slider-crank mechanism formed by connecting the additional circular gear and the piston by the connecting rod provides a link between the rotational movement of the wheel and the back and forth movement of the pump member.

[10] The pump member includes a piston that fits into an inner diameter of the tubular cavity and is movable back and forth within the tubular cavity, and a connecting rod that is connected to the piston and extends to a side opposite the tubular cavity, The rotation axis of the wheel is fixed to the body, and the wheel has a pin at a position offset from the rotation axis, the connecting rod is coupled to a yoke including a slot at an end opposite the end coupled to the piston; a scotch yoke mechanism formed by a pin on the wheel engaging in the slot provides a link between the rotational movement of the wheel and the back and forth movement of the pump member; The micropipette system according to [1] or [2].

[11]

[10] The micropipette system according to the present invention, the micropipette system includes a circular gear that rotates in unison with the wheel, and one or more additional circular gears that engage with the circular gear; the pin that engages with the slot of the yoke is located off-axis on one of the one or more additional circular gears but not on the wheel; A micropipette system wherein a scotch yoke mechanism formed by a pin on the additional circular gear engaging in the slot provides coupling between the rotational movement of the wheel and the back and forth movement of the pump member.

[12] The micropipette system described in any of [1] to

[11] , wherein the microcapillary needle is based on a Pasteur pipette, the tip of the Pasteur pipette forms a needle and the end is fixed to the body.

[13] The micropipette system according to any one of [1] to

[12] , wherein the microcapillary needle is removable from the body and replaceable.

[14] a barrel having a longitudinal axis and proximal and distal ends, the barrel having a tubular cavity extending along at least a portion of the longitudinal axis; a rotatable wheel having an axis of rotation in a proximal region of the torso; a pump member configured to move back and forth in a distal or proximal direction within the body in response to rotational movement of the wheel; a microcapillary needle insertion port that opens in a proximal direction to receive a microcapillary needle that extends proximally from the barrel; A micropipettor comprising: an outer edge of the wheel is at least partially exposed from the body portion; the microcapillary needle insertion port communicates with the tubular cavity of the body; the back and forth movement of the pump member increases or decreases the volume of the tubular cavity, thereby allowing the intake or exhaust of fluid in the internal space of a microcapillary needle inserted into the microcapillary needle insertion port. Micropipettor.

[15] A micropipette kit comprising the micropipette according to

[14] and a microcapillary needle.

[16] The micropipette system according to any one of [1] to

[13] is formed by receiving a microcapillary needle in the microcapillary needle insertion port. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows the appearance of a micropipette system according to one embodiment held in a "pencil grip" by an operator's hand. [Diagram 2]Figure 2 shows diagrammatically an embodiment in which the link between the rotational movement of the wheel and the back and forth movement of the pump member is provided on the basis of a rack and pinion mechanism. Embodiments are shown that do not include (a) or that include (b-d) an additional circular gear. [Diagram 3] FIG. 3 shows a schematic representation of an embodiment in which the wheel rim itself constitutes the pump member based on a peristaltic pump mechanism. [Figure 4] FIG. 4 shows a schematic of an embodiment in which movement of the wheel along the barrel-fixed linear gear also moves the pump member via a connecting rod, thereby providing a link between the rotational movement of the wheel and the back and forth movement of the pump member. [Diagram 5] FIG. 5 shows diagrammatically an embodiment in which the link between the rotational movement of the wheel and the back and forth movement of the pump member is provided on the basis of a slider-crank mechanism. [Figure 6] FIG. 6 shows diagrammatically an embodiment in which the link between the rotational movement of the wheel and the back and forth movement of the pump member is provided on the basis of a Scotch yoke mechanism. [Figure 7] FIG. 7 shows an example of an embodiment in which the end of a microcapillary needle is inserted into a microcapillary needle insertion port. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] [Micropipette system] The micropipette system of the present disclosure will be described with reference to the drawings, which are non-limiting examples. In one aspect, the present disclosure provides a micropipette system 1. A micropipette generally means a pipette for aspirating and discharging fluids on a microliter scale or less. For example, a pipette that is usually used for embryo manipulation is a micropipette. As shown in FIG. 1, the micropipette system of this embodiment has a body 10 having a long axis 10a, a proximal end 10b, and a distal end 10c. The long axis here refers to an axis that is defined conceptually, not a physical structure. It is understood that the body is typically elongated, and that the length along the long axis is greater than the thickness. In the present disclosure, "proximal" means closer to the sample along the long axis when manipulating a sample such as an embryo with the micropipette system, and "distal" means farther from the sample. The proximal end of the pipette can also be called the tip of the pipette, and the distal end of the pipette can also be called the end of the pipette. In the accompanying drawings, the micropipette system 1 is shown with the proximal direction oriented to the left (x) and the distal direction oriented to the right (y).

[0014] As not visible in Figure 1 but shown in Figures 2-6, the body of the micropipette system of this embodiment has a tubular cavity 11 that extends along at least a portion of its long axis 10a. By the tubular cavity extending along the long axis, we mean that the tubular cavity extends generally parallel to the long axis.

[0015] The micropipette system of this embodiment includes a rotatable wheel 20, the axis of rotation 21 of which is located in the proximal region of the body 10, i.e., proximal to the center. In a preferred embodiment, the axis of rotation 21 of the wheel 20 is located within a third or a quarter of the total length of the body from the proximal end. The axis of rotation 21 of the wheel is preferably generally perpendicular to the longitudinal axis 10a of the body. The diameter of the wheel is typically within the range of 1 to 5 cm, more typically within the range of 1.5 to 4 cm.

[0016] The outer edge 22 of the wheel 20 is at least partially exposed from the body 10. Thus, an operator of the micropipette system 1 can hold the body 10 in one hand and touch the outer edge 22 of the wheel 20 with one finger of that hand to rotate the wheel 20 back and forth with the force of the finger.

[0017] The micropipette system 1 of this embodiment is a handheld type micropipette system. The micropipette system 1 of this embodiment has the advantage that it can be held in a "pencil grip" and intuitively controlled with the index finger (or thumb, or middle finger). This advantage is based on the fact that the rotation axis of the wheel is in the proximal region. "Pencil grip" is a common expression in Japanese, and means a normal hand shape for holding a writing instrument such as a pencil or pen. That is, as shown in FIG. 1, when the micropipette system of this embodiment is held in a pencil grip, the body 10 is held at least three points (or four points including the base of the index finger) on the pads of the index finger and thumb (where the fingerprints are) and the inside of the middle finger (the side that usually contacts the index finger), and then, without substantially changing the shape of the hand, the index finger can be used to touch the wheel 20 and rotate it at will, allowing delicate control of the intake and discharge of fluid in the microcapillary needle 40. The inventors have found that the combination of this "pencil grip" and a wheel that can be rotated and controlled with a single index finger significantly improves the intuitiveness, reliability, and efficiency of embryo manipulation. The intuitiveness of operation with this micropipette system is comparable to that of a mouthpiece type. Furthermore, the micropipette system of this embodiment is not subject to the potential safety issues associated with the mouthpiece type.

[0018] The wheel 20 is preferably not spring-loaded. Spring-loaded means that a spring is involved so that a displaced member returns to its original position due to the elasticity of the spring. In conventional thumb-controlled micropipettes, the rod portion protruding in the distal direction is spring-loaded. This is because it is easy for the thumb of an operator holding a thumb-controlled micropipette to push the rod portion but difficult to pull it. This reliance on springs, i.e., reliance on elasticity, is one of the factors that relatively reduce the intuitiveness or delicacy of the operation. In the micropipette system of this embodiment, it is possible but not necessary to make the wheel or other members spring-loaded.

[0019] The length of the body 10 is typically within the range of 5 to 20 cm, and preferably within the range of 6 to 18 cm, or 7 to 16 cm. The diameter of the part of the body 10 that comes into contact with the hand during normal use of the micropipette system is typically within the range of 1.5 to 5 cm.

[0020] The micropipette system 1 of this embodiment includes a pump member 30 configured to move back and forth in a distal or proximal direction in the body 10 in conjunction with the rotational movement of the wheel 20. In this disclosure, "rotational movement" or "rotation" means moving only at a certain angle while being constrained by the axis of rotation, and does not necessarily have to rotate 360°. In fact, the rotation angle corresponding to the adjustment of a microliter-scale amount of fluid may typically be less than 180°. There are many known mechanisms that can convert the rotational movement of one member into the linear movement of another member, and these can be used in this embodiment. It is generally understood that when an object rotates back and forth (i.e., in one rotation direction and in the opposite rotation direction), the part away from the axis of rotation moves back and forth in an arc. The mechanism for converting rotational movement into linear movement can utilize such basic properties in various ways. Non-limiting examples are described herein.

[0021] The micropipette system 1 of this embodiment further includes a microcapillary needle 40 extending proximally from the body 10. As will be understood by those skilled in the art of embryo manipulation, a microcapillary needle refers to a hollow tube whose tip is typically tapered to an inner diameter of 600 μm or less (e.g., 50-600 μm, or 75-300 μm) to form a needle. The microcapillary needle is typically transparent. The material of the microcapillary needle is preferably, but not limited to, glass, and may be, for example, a plastic such as polycarbonate. As will be known to those skilled in the art, for example, a Pasteur pipette or a capillary tube can be heated and stretched thin, and then appropriately processed (e.g., trimmed) to adjust the diameter and / or shape of the tip to produce a microcapillary needle. In some embodiments, the microcapillary needle 40 is based on a Pasteur pipette, the tip of which forms the needle, and the end is attached to the body 10. A Pasteur pipette, as will be understood by those skilled in the art, is a pipette, typically made of glass, that is usually used with a rubber bulb at the end. The end of a microcapillary needle usually has a significantly larger outer and inner diameter than the tip. For example, in the case of a microcapillary needle based on a Pasteur pipette, the original end of the Pasteur pipette, where the rubber bulb would normally be attached, may be the end of the microcapillary needle 40.

[0022] The microcapillary needle 40 has an internal space 41 that communicates with the tubular cavity 11 of the body. The back and forth movement of the pump member 30 increases and decreases the volume of the tubular cavity 11, thereby allowing the intake or discharge of fluid in the internal space of the microcapillary needle 40. It has been found that by holding the body 10 like a pencil and rotating the wheel 20 having a rotation axis in the proximal region of the body with a finger, the operator's intuitive intention, the change in the volume of the tubular cavity, and the intake or discharge of a microliter-scale amount of fluid in the microcapillary needle can be precisely coordinated.

[0023] In a particularly preferred embodiment, the tubular cavity 11 of the body extends distally relative to the pump member 30, and the tubular cavity 11 and the internal space 41 of the microcapillary needle are connected by a conduit 50 that makes a U-turn from the distal direction to the proximal direction. This embodiment is preferable because, compared with an embodiment in which the tubular cavity extends proximally relative to the pump member and directly connects to the microcapillary needle, the presence of an additional volume provides a moderate cushion, which significantly improves the fine adjustment of the amount of fluid according to the operator's intention, and does not impede the ease of holding and compactness of the micropipette system as a whole. The "U-turn" means that the conduit extending in the distal direction turns proximally halfway and connects to the microcapillary needle, and the shape does not have to be literally U-shaped. For example, the U-turning conduit may be a tube (e.g., a flexible tube such as a rubber tube) connected to the body 10 and exposed to the outside of the body. Alternatively, the U-turn conduit may be a cavity or tube integrated inside the body 10 as illustrated in the drawings.

[0024] The microcapillary needle 40 of the micropipette system 1 of the present disclosure is preferably removable and replaceable from the body 10. In the present disclosure, a product from which the microcapillary needle 40 has been removed is specifically referred to as a "micropipettor." By attaching a microcapillary needle to the micropipettor, a micropipette that can be used for embryo manipulation and the like is formed.

[0025] A non-limiting example of a mechanism for moving pump member 30 back and forth distally or proximally within body 10 in conjunction with rotational movement of wheel 20 will now be described.

[0026] In the embodiment shown in FIG. 2, the pump member 30 has a piston 31 that fits into the inner diameter of the tubular cavity 11 and can move back and forth in the tubular cavity 11, and a linear gear 32 that is connected to the piston 31 and extends on the opposite side of the tubular cavity (i.e., the tubular cavity that communicates with the internal space 41 of the microcapillary needle). This micropipette system includes a circular gear 23 that rotates together with the wheel 20. In one example, as shown in FIG. 2a and b, the circular gear 23 that is concentric with the wheel 20 may be connected to the wheel 20. In another example, as shown in FIG. 2c and d, the wheel 20 itself may be the circular gear 23. In this case, the operator operates the wheel by touching the teeth of the circular gear 23 / 20 with his / her fingers. The rotation axis 21 of the wheel is fixed to the body. The rotation axis being "fixed" means that the position of the rotation axis is fixed, and the rotation of the wheel, etc. occurs at that position. In these embodiments, the back and forth movement of the pump member is based on a rack and pinion mechanism by the engagement of the circular gear 23 with the linear gear 32, providing a link between the rotational movement of the wheel and the back and forth movement of the pump member. The piston 31 may include a gasket portion and a plunger portion that are responsible for fitting to the inner diameter of the tubular cavity, like the piston of a syringe (illustrated in Figs. 2c and d, but applicable to other embodiments as well).

[0027] The engagement between the circular gear 23 and the linear gear 32 in the rack-and-pinion mechanism may be indirect engagement via one or more additional circular gears 60 engaged between the circular gear 23 and the linear gear 32, as shown in Figs. 2b-d. In that case, one of the one or more additional circular gears 60, rather than the circular gear 23 itself, directly engages with the linear gear 32. In the present disclosure, when there are multiple additional circular gears, the additional circular gears "engage" with the circular gears means that the circular gear directly engages with the first additional circular gear, the first additional circular gear directly engages with the second additional circular gear, and so on. The last additional circular gear directly engages with the linear gear 32. As illustrated in Fig. 2d, the additional circular gear 60 may include two or more gears concentrically coupled together, so that the gear engaged with the preceding circular gear and the gear engaged with the succeeding circular gear (or linear gear) in one additional circular gear 60 may be different. The terms "leading" and "following" used here indicate that the rotation of the wheel 20 by a finger is the starting point, i.e., the foremost point, from which the movement of the gear is propagated.

[0028] In an embodiment in which the upper outer edge 22 of the wheel 20 is exposed from the body 10 and the engagement with the linear gear 32 occurs under the additional circular gear 60 as in the examples of Figs. 2b-d, when the number of the additional circular gears 60 is one or an odd number, the rotational movement of the wheel 20 and the back-and-forth movement of the pump member 30 are linked in the opposite direction compared to when there is no additional circular gear 60. When the number of the additional circular gears 60 is two or an even number, the rotational movement of the wheel 20 and the back-and-forth movement of the pump member 30 are linked in the same direction compared to when there is no additional circular gear 60. In a particular preferred embodiment, as shown in Figs. 2b-d, the tubular cavity 11 and the internal space 41 of the microcapillary needle are communicated by a conduit 50 that makes a U-turn, and the number of the additional circular gears 60 is one or an odd number. It is understood that the rotational axis of each of the one or more additional circular gears 60 is typically fixed to the body.

[0029] The one or more additional circular gears 60 can thus change the direction of the link between the rotational movement of the wheel 20 and the back and forth movement of the pump member 30. This allows the relationship between the rotational direction of the wheel 20 and the direction of the liquid entering and leaving the microcapillary needle to be optimized to better suit the intuition of an individual user. In this way, the additional circular gears 60 can serve to reverse the movement direction of the pump member 30 relative to the rotational direction of the wheel 20 or to bridge the distance between the circular gear 23 and the linear gear 32, but can be provided as "idler gears" that do not necessarily affect the movement distance of the piston 31 in response to the rotation of the wheel 20.

[0030] As illustrated in FIG. 2a, an embodiment in which the diameter of the circular gear 23, which is concentric with the wheel 20 and engages with the linear gear 32, is smaller than the diameter of the wheel 20 (for example, 2 / 3 or less, 1 / 2 or less, or 1 / 3 or less (typically 1 / 10 or more)) is particularly preferred for fine operability by finger movement. Specifically, the smaller the diameter of the circular gear 23 is compared to the diameter of the wheel 20, the relatively fewer the number of gear teeth the circular gear 23 has, and the moving distance of the linear gear 32 caused by rotating the wheel 20 is expressed as "the moving distance in the circumferential direction of the outer edge of the wheel 20" x "the diameter of the circular gear 23 / the diameter of the wheel 20". Therefore, the greater the difference between the diameters of the two, the shorter the moving distance of the linear gear 32 per the same rotation angle of the wheel 20, and the slower the linear motion of the linear gear 32 is. In other words, the greater the difference between the diameters of the two, the weaker the force that can be used to operate the piston 31 and the easier it is to adjust fine movements. Accordingly, the movement of the air or liquid near the tip of the microcapillary needle 40 is also slowed down, ultimately improving the fine operability of handling liquid containing an embryo or the like.

[0031] In a preferred example of the embodiment shown in FIG. 2a, the wheel 20 has two layers of wheel discs of the same diameter, sandwiching the circular gear 23, the linear gear 32 also extends between the two layers, and the engagement between the linear gear 32 and the circular gear 23 occurs between the two layers of wheel discs. The reason why such an embodiment is preferred is that sandwiching the linear gear 32 between two layers of wheel discs can prevent the linear gear from falling over or deviating from its track, and can stabilize the linear gear 32 moving back and forth on its linear track. However, this is merely one example of a configuration for stabilizing the linear motion of the linear gear 32, and is not limited thereto. For example, instead of sandwiching the linear gear 32 between two layers of wheel discs, it is also possible to prevent the linear gear 32 from falling over or deviating from its track during operation by providing a support structure that supports the linear gear 32 from the side opposite to the circular gear 23 or from the bottom. The smaller the area of ​​the bottom portion of the linear gear 32 that comes into contact with the body 10 when the linear gear 32 moves linearly, the weaker the frictional resistance becomes, making it possible to operate it with less force.

[0032] In the example of FIG. 2b, an embodiment in which the diameter of the circular gear 23 that engages with the additional circular gear 60 is smaller than the diameter of the wheel 20 (for example, 2 / 3 or less, 1 / 2 or less, or 1 / 3 or less (typically 1 / 10 or more)) is particularly preferred for fine operability by finger movement. As described with reference to FIG. 2a, the smaller the diameter of the circular gear 23 is compared to the diameter of the wheel 20, the relatively fewer the number of gear teeth that the circular gear 23 has, and the number of gear teeth or arc length involved in engagement per the same rotation angle of the wheel 20 is reduced, so that the moving distance of the linear gear 32 is shortened and the linear motion of the linear gear 32 is decelerated. In other words, the greater the difference between the diameters of the two, the weaker the force required to operate the piston 31 and the easier it is to adjust fine movements. As described above, this leads to improved fine operability in handling liquids containing embryos, etc.

[0033] In a preferred embodiment shown in Fig. 2b, the wheel 20 has two layers of wheel discs of the same diameter, sandwiching the circular gear 23, and the additional circular gear 60 is inserted between the two layers of wheel discs and engages with the circular gear 23. It is also possible to arrange the linear gear 32 so that it extends between the two layers of wheel discs. However, the configuration of having two layers of wheel discs and sandwiching the additional circular gear and / or linear gear therebetween is only one example for stabilizing and strengthening the mechanism, and other configurations such as those described above are also possible.

[0034] In a preferred example of the embodiment shown in Fig. 2c, the circular gear 23 includes two layers of gears of the same diameter (so that the cross section including the shaft 21 is H-shaped), the linear gear 32 extends between the two layers, and the additional circular gear 60 is cylindrical and engages with the two layers of gears and the linear gear. This is only one non-limiting example to stabilize and robust the mechanism.

[0035] As illustrated in FIG. 2d, an embodiment is preferred in which the additional circular gear 60 includes two gears coupled concentrically, and the diameter of the gear that engages with the linear gear 32 is smaller than the diameter of the gear that engages with the circular gear 23 (for example, 2 / 3 or less, 1 / 2 or less, or 1 / 3 or less (typically 1 / 10 or more)). The relationship between these two gears coupled to each other is similar to the relationship between the wheel 20 and the circular gear 23 described with reference to FIGS. 2a and 2b. In other words, when the diameter of the gear that engages with the subsequent gear is reduced compared to the diameter of the gear that engages with the preceding gear, a conversion occurs in which the number of gear teeth or arc length involved in engagement is reduced in the additional circular gear 60, and therefore the moving distance of the linear gear 32 is also shortened, and the linear motion of the linear gear 32 is decelerated. This allows the piston 31 to be operated with a weak force and makes it easier to adjust fine movements.

[0036] In the embodiment shown diagrammatically in Fig. 3, the tubular cavity 11 is provided at least in part by a flexible tube section 11a. A second wheel 24 is coupled to the wheel 20, rotating concentrically with the wheel 20, one of the wheels 20 and the second wheel 24 (second wheel 24 in Fig. 3) forming a circular gear 25. The body 10 includes a body fixed linear gear 12 extending along the longitudinal axis 10a and fixed to the body 10, engaging the circular gear 25. When the wheel 20 and the second wheel 24 rotate, the circular gear 25 rolls on the trunk-fixed linear gear 12, and the outer edge 26 of the wheel 20 or the second wheel 24 that does not constitute the circular gear 25 (the wheel 20 in FIG. 3) contacts the flexible tube region 11a externally and presses the tubular cavity in the flexible tube region, so that the wheel outer edge 26 in contact with the flexible tube region 11a itself constitutes a pump member 30 based on a peristaltic pump mechanism that moves back and forth in conjunction with the rotational movement of the wheel 20. The trunk 10 of the present disclosure may be generally cylindrical, box-like, or case-like. Typically, the trunk-fixed linear gear 12 is fixed inside such a trunk 10, and the inside of the trunk 10 may further have an axis guide 13 that defines the movement range of the rotation axis 21 of the wheel. The axis guide 13 may be a window that opens to the outside of the trunk 10. In the embodiment shown in Fig. 3, the trunk-fixed linear gear 12 extends parallel to the longitudinal axis of the trunk 10, but the trunk-fixed linear gear 12 may be inclined with respect to the longitudinal axis of the trunk. For example, in Fig. 3, when the trunk-fixed linear gear 12 is inclined toward the distal direction, the pump member 30 presses the flexible tube region 11a more strongly as the wheel 20 is rotated and moved in the distal direction.

[0037] In the embodiment shown in FIG. 4, the pump member 30 has a piston 33 that fits into the inner diameter of the tubular cavity 11 and can move back and forth within the tubular cavity 11, and a connecting rod 34 that is connected to the piston 33 and extends to the opposite side of the tubular cavity 11, and the connecting rod 34 is fixed to the rotation axis 21 of the wheel 20 at the end opposite to the end connected to the piston 33. The micropipette system in these embodiments includes a circular gear 27 that rotates integrally with the wheel 20. As in the case of the rack and pinion mechanism described above, the wheel 20 itself may be the circular gear 27, or a circular gear 27 concentric with the wheel 20 may be connected to the wheel as shown in FIG. 4. The body 10 includes a body-fixed linear gear 14 extending along the long axis 10a and fixed to the body 10 and engaging with the circular gear 27, and when the wheel 20 rotates, the circular gear 27 rolls on the body-fixed linear gear 14, and the movement of the wheel 20 along the body-fixed linear gear 14 also moves the pump member 30 (particularly, the piston 33) via the connecting rod 34, thereby providing a link between the rotational movement of the wheel and the back and forth movement of the pump member.

[0038] In the embodiment involving a fixed barrel linear gear as shown in Figures 3 and 4, rotation of the wheel 20 causes the wheel 20 itself to move in a distal or proximal direction, but the small distance of movement corresponding to microliter-scale fluid volumes allows the operator to operate the micropipette system 1 via the wheel 20 while still maintaining a substantially pencil-like grip.

[0039] In the embodiment shown in FIG. 5, the pump member 30 has a piston 35 that fits into the inner diameter of the tubular cavity 11 and can move back and forth within the tubular cavity 11, a connecting rod 36 is fixed to the piston 35 and extends to the opposite side of the tubular cavity 11, the rotation axis 21 of the wheel 20 is fixed to the body, and the connecting rod 36 is fixed at an end opposite to the end fixed to the piston 35 at a position on the wheel 20 that is off the rotation axis. In these embodiments, a slider crank mechanism formed by connecting the wheel 20 and the piston 35 with the connecting rod 36 provides a link between the rotational movement of the wheel and the back and forth movement of the pump member. It is understood that the fixing of the rod 36 to the wheel 20 and the piston 35 is a fixing that allows rotation or swinging, respectively. Alternatively, a variation of the micropipette system utilizing the slider-crank mechanism described above may have a circular gear that rotates together with the wheel 20 and one or more additional circular gears that engage with the circular gear, and the connecting rod 36 is fixed at an end opposite to the end fixed to the piston 35 to a position off the axis of rotation of one of the one or more additional circular gears (rather than the wheel 20). The axis of rotation of the additional circular gear may be fixed to the barrel. The significance and variations of the additional circular gears are similar to those described with respect to the embodiment of FIG. 2.

[0040] In the embodiment shown in FIG. 6, the pump member 30 has a piston 37 that fits into the inner diameter of the tubular cavity 11 and can move back and forth within the tubular cavity 11, and a connecting rod 38 that is connected to the piston 37 and extends on the opposite side of the tubular cavity 11, the rotation axis 21 of the wheel 20 is fixed to the body, the wheel 20 has a pin 70 at a position offset from the rotation axis 21, and the connecting rod 38 is connected to a yoke 71 including a slot at an end opposite to the end connected to the piston 37. In these embodiments, a Scotch yoke mechanism formed by the pin 70 on the wheel 20 engaging in the slot provides a link between the rotational movement of the wheel and the back and forth movement of the pump member. Alternatively, a variation of the micropipette system using the above Scotch yoke mechanism has a circular gear that rotates together with the wheel 20 and one or more additional circular gears that engage with the circular gear, and the pin 70 that engages with the slot of the yoke 71 is located at a position offset from the rotation axis on one of the one or more additional circular gears (not the wheel 20). The rotation axis of the additional circular gear may be fixed to the barrel. The meaning and variations of the additional circular gear are similar to those described with respect to the embodiment of FIG.

[0041] [Micropipette] In another aspect, the present disclosure provides a micropipettor. The micropipettor of this embodiment can be understood to essentially correspond to any of the micropipette systems described above, prior to the attachment of a microcapillary needle 40. The micropipettor has an insertion port 80 for receiving a microcapillary needle 40. Thus, in a basic embodiment, the micropipettor includes a body having a long axis and proximal and distal ends, and a tubular cavity extending along at least a portion of said long axis, a rotatable wheel having an axis of rotation in a proximal region of said body, a pump member configured to move distally or proximally back and forth in said body in conjunction with the rotational movement of said wheel, and a microcapillary needle insertion port opening proximally to receive a microcapillary needle extending proximally from said body. An outer edge of the wheel is at least partially exposed from the body. It should be understood that the structural and functional descriptions provided for the various embodiments of the micropipette system may each be applied to the corresponding micropipettor. The microcapillary needle insertion port 80 communicates with the tubular cavity of the body, and the back and forth movement of the pump member increases and decreases the volume of the tubular cavity, thereby allowing the intake or exhaust of fluid in the internal space 41 of the microcapillary needle when the microcapillary needle 40 is inserted into the microcapillary needle insertion port 80.

[0042] The shape of the microcapillary needle insertion port 80 is not particularly limited as long as it can achieve airtightness between the inserted microcapillary needle and the micropipettor, and can be appropriately determined by a person skilled in the art according to the shape and size of the end of the microcapillary needle to be used. For example, in the example shown in the schematic cross-sectional view of FIG. 7a, the microcapillary needle insertion port 80 has a tapered internal shape so that the end of the microcapillary needle 40 (such as one based on a Pasteur pipette) can be pushed in to achieve airtight communication. Alternatively, the microcapillary needle insertion port 80 may have an O-ring 81 such as rubber so that the end of the microcapillary needle 40 can be pushed in to achieve airtight communication, as in the example shown in the schematic cross-sectional view of FIG. 7b. In a preferred embodiment, the microcapillary needle 40 is based on a Pasteur pipette, and the microcapillary needle insertion port 80 is located distal to the rotation axis 21 of the wheel 20. Such an arrangement is preferable because it can provide an overall shape of the micropipette system that is optimal for operation with the wheel 20 while holding it with a pencil.

[0043] [Micropipette kit] In another aspect, the present disclosure provides a micropipette kit including any one of the micropipettors described above and a microcapillary needle. A user can prepare a usable micropipette system by inserting the end of the microcapillary needle provided in the kit into the microcapillary needle insertion port of the micropipettor.

[0044] Various embodiments of the micropipette systems, micropipettors, and micropipette kits of the present disclosure find particular utility in fields such as assisted human reproduction, livestock breeding technology, and laboratory animal reproductive engineering, but may also be useful in a variety of other technical fields requiring delicate manipulation of microliter-scale or submicroliter volumes of fluids or particulate suspensions. [Explanation of symbols]

[0045] 1 Micropipette system 10. Torso 20 Wheels 30 Pump parts 40 Microcapillary Needle 50 U-Turn Conduit 60 additional circular gears 80 Microcapillary needle insertion port

Claims

1. a barrel having a longitudinal axis and proximal and distal ends, the barrel having a tubular cavity extending along at least a portion of the longitudinal axis; a rotatable wheel having an axis of rotation in a proximal region of the torso; a pump member configured to move back and forth in a distal or proximal direction within the body in response to rotational movement of the wheel; a microcapillary needle extending proximally from the barrel; A micropipette system comprising: an outer edge of the wheel is at least partially exposed from the body portion; the microcapillary needle has an internal space communicating with the tubular cavity of the body; the back and forth movement of the pump member increases or decreases the volume of the tubular cavity, thereby allowing the intake or exhaust of fluid in the interior space of the microcapillary needle. Micropipette system.

2. 2. The micropipette system of claim 1, wherein the tubular cavity extends distally of the pump member, and the tubular cavity and the interior space of the microcapillary needle are connected by a conduit that makes a U-turn from the distal direction to the proximal direction.

3. The pump member has a piston that fits into the inner diameter of the tubular cavity and is movable back and forth within the tubular cavity, and a linear gear that is connected to the piston and extends to a side opposite the tubular cavity, The micropipette system includes a circular gear that rotates together with the wheel, and the rotation axis of the wheel is fixed to the body; The back and forth movement of the pump member based on a rack and pinion mechanism caused by the engagement between the circular gear and the linear gear provides a link between the rotational movement of the wheel and the back and forth movement of the pump member.

2. The micropipette system of claim 1.

4. the engagement between the circular gear and the linear gear in the rack-and-pinion mechanism is indirect engagement via one or more additional circular gears engaged between the circular gear and the linear gear; 4. The micropipette system of claim 3, wherein one of the one or more additional circular gears, rather than the circular gear, directly engages the linear gear.

5. 5. The micropipette system of claim 3, wherein the circular gear is concentric with and connected to the wheel, and the diameter of the circular gear is less than or equal to 2 / 3 of the diameter of the wheel.

6. the tubular cavity being provided, at least in part, by a flexible tubing region; a second wheel is coupled to the wheel and rotates concentrically therewith, one of the wheel and the second wheel forming a circular gear; the barrel includes a barrel-fixed linear gear extending along the longitudinal axis and fixed to the barrel and engaging the circular gear; When the wheel and the second wheel rotate, the circular gear rolls on the trunk-fixed linear gear, and the circular gear and the second wheel move along the trunk-fixed linear gear, an outer edge of the wheel not constituting the circular gear out of the wheel and the second wheel is in circumscribing the flexible tube region and compressing a tubular cavity in the flexible tube region, so that the outer edge of the wheel itself constitutes a pump member based on a peristaltic pump mechanism that moves back and forth in conjunction with the rotational movement of the wheel.

2. The micropipette system of claim 1.

7. The pump member includes a piston that fits into an inner diameter of the tubular cavity and is movable back and forth within the tubular cavity, and a connecting rod that is connected to the piston and extends to a side opposite the tubular cavity, The connecting rod is fixed to a rotation axis of the wheel at an end opposite to the end connected to the piston, the micropipette system includes a circular gear that rotates in unison with the wheel; the barrel includes a barrel-fixed linear gear extending along the longitudinal axis and fixed to the barrel and engaging the circular gear; When the wheel rotates, the circular gear rolls on the linear gear fixed to the body, and the wheel moves along the linear gear fixed to the body; The movement of the wheel along the body fixed linear gear also moves the pump member via the connecting rod, thereby providing a link between the rotational movement of the wheel and the back and forth movement of the pump member.

2. The micropipette system of claim 1.

8. the pump member has a piston that fits into an inner diameter of the tubular cavity and is movable back and forth within the tubular cavity, the piston having a connecting rod fixed thereto and extending to a side opposite the tubular cavity; The rotation axis of the wheel is fixed to the body, the connecting rod is fixed at an end opposite to the end fixed to the piston to a position on the wheel offset from the rotation axis; A slider-crank mechanism formed by connecting the wheel and the piston with the connecting rod provides a link between the rotational movement of the wheel and the back-and-forth movement of the pump member.

2. The micropipette system of claim 1.

9. 9. The micropipette system according to claim 8, the micropipette system includes a circular gear that rotates in unison with the wheel, and one or more additional circular gears that engage with the circular gear; the connecting rod is fixed at an end opposite to the end fixed to the piston at a position offset from the axis of rotation of one of the one or more additional circular gears rather than the wheel; A micropipette system, wherein a slider-crank mechanism formed by connecting the additional circular gear and the piston by the connecting rod provides a link between the rotational movement of the wheel and the back and forth movement of the pump member.

10. The pump member includes a piston that fits into an inner diameter of the tubular cavity and is movable back and forth within the tubular cavity, and a connecting rod that is connected to the piston and extends to a side opposite the tubular cavity, The rotation axis of the wheel is fixed to the body, and the wheel has a pin at a position offset from the rotation axis, the connecting rod is coupled to a yoke including a slot at an end opposite the end coupled to the piston; a scotch yoke mechanism formed by a pin on the wheel engaging in the slot provides a link between the rotational movement of the wheel and the back and forth movement of the pump member; 2. The micropipette system of claim 1.

11. 11. The micropipette system according to claim 10, the micropipette system includes a circular gear that rotates in unison with the wheel, and one or more additional circular gears that engage with the circular gear; the pin that engages with the slot of the yoke is located off-axis on one of the one or more additional circular gears but not on the wheel; A micropipette system wherein a scotch yoke mechanism formed by a pin on the additional circular gear engaging in the slot provides coupling between the rotational movement of the wheel and the back and forth movement of the pump member.

12. 2. The micropipette system of claim 1, wherein the microcapillary needle is based on a Pasteur pipette, the tip of the Pasteur pipette forming a needle and the end being fixed to the body.

13. The micropipette system of claim 1 , wherein the microcapillary needle is removable and replaceable from the body.

14. a barrel having a longitudinal axis and proximal and distal ends, the barrel having a tubular cavity extending along at least a portion of the longitudinal axis; a rotatable wheel having an axis of rotation in a proximal region of the torso; a pump member configured to move back and forth in a distal or proximal direction within the body in response to rotational movement of the wheel; a microcapillary needle insertion port that opens in a proximal direction to receive a microcapillary needle that extends proximally from the barrel; A micropipettor comprising: an outer edge of the wheel is at least partially exposed from the body portion; the microcapillary needle insertion port communicates with the tubular cavity of the body; the back and forth movement of the pump member increases or decreases the volume of the tubular cavity, thereby allowing the intake or exhaust of fluid in the internal space of a microcapillary needle inserted into the microcapillary needle insertion port. Micropipettor.

15. A micropipette kit comprising the micropipettor according to claim 14 and a microcapillary needle.

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