WO2009008843A1

WO2009008843A1 - Apparatus for forming a tissue array

Info

Publication number: WO2009008843A1
Application number: PCT/SG2008/000251
Authority: WO
Inventors: Manuel Salto-Tellez; Lay Gek Kim; Kok Kiong Tan; Andi Sudjana Putra
Original assignee: National University of Singapore
Current assignee: National University of Singapore
Priority date: 2007-07-10
Filing date: 2008-07-14
Publication date: 2009-01-15
Anticipated expiration: 2010-01-10

Abstract

The invention provides an apparatus for forming a tissue array in an at least substantially solid recipient. The apparatus comprises an extractor member with a stylus and a tubular end portion with an opening for accommodating a tissue sample. The apparatus also comprises a punch member comprising a stylus and a tubular end portion with an opening for accommodating matter punched by the edge from the recipient. The apparatus also comprises a housing that comprising a first guiding means and a second guiding means. The first guiding means provides fixation to the stylus of the extractor member inside the housing in the axial direction, and the second guiding means providing fixation to the stylus of the punch member inside the housing in the axial direction. Further, the punch member is in communication with a punch actuator and the extractor member is in communication with an extractor actuator.

Description

APPARATUS FOR FORMING A TISSUE ARRAY

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application makes reference to and claims the benefit of priority of an application for a "Tissue Portable Arrayer System" filed on July 10, 2007 with the United States Patent and Trademark Office, and there duly assigned serial number 60/958,892. The contents of said application filed on July 10, 2007 is incorporated herein by reference for all purposes, including an incorporation of any element or part of the description, claims or drawings not contained herein and referred to in Rule 20.5(a) of the PCT, pursuant to Rule 4.18 of the PCT.

FIELD OF THE INVENTION

[0002] The present invention relates to an apparatus for forming a tissue array. Provided is also the use of the apparatus in forming a tissue array.

BACKGROUND OF THE INVENTION

[0003] Tissue micro-arrays allow examining large pluralities of tissues with an economical use of material and technical resources. Tissue micro-array (TMA) technology provides economy in terms of time, reagents, tissue specimens and laboratory capacity. From a single donor block with a large number of tissue portions, e.g. 1000 biopsy samples, multiple, e.g. 200, identical tissue micro-arrays can be prepared. The tissue samples may for instance be frozen or formalin-fixed and the TMA ensures experimental uniformity.

[0004] To date, TMA technology in general, and devices for forming a tissue array in particular, have been based on two extremes. On the one hand, there are very sophisticated tissue array forming devices, herein also referred to as tissue arrayers, which, at a significant cost, provide bulky machinery to perform a relatively easy task. On the other end of the spectrum, we have very simple and non-durable needle devices which are difficult to manipulate in an accurate fashion. Hence, an affordable and yet reliable tissue arrayer to perform TMA is in need. [0005] Tissue arrayer models at the high-end of the spectrum are of bulky size, and relatively complex in operating. They further lack transportability and are of relatively high cost for a technology of certain simplicity. [0006] Accordingly, it is an object of the present invention to provide an apparatus or device for forming a tissue array that overcomes at least some of these disadvantages. In a particular aspect it is an object of the invention to provide a portable, affordable and yet accurate and easy-to-use alternative to present TMA construction.

SUMMARY OF THE INVENTION

[0007] According to a first aspect, the invention provides an apparatus for forming a tissue array in an at least substantially solid recipient. The apparatus includes an extractor member. The extractor member includes a stylus. The extractor member also includes a tubular end portion for accommodating a tissue sample. The tubular end portion has an opening. Further, the apparatus includes a punch member. The punch member includes a stylus. The punch member also includes a tubular end portion for accommodating matter punched from the recipient. The tubular end portion has an opening. The apparatus also includes a housing. The housing includes a first guiding means and a second guiding means. The first guiding means provides fixation to the stylus of the extractor member inside the housing. As a result the stylus of the extractor member is movable in the axial direction. The second guiding means provides fixation to the stylus of the punch member inside the housing. As a result the stylus of the punch member is movable in the axial direction. The punch member is in communication with a punch actuator. The extractor member is in communication with an extractor actuator. [0008] According to a second aspect, the invention provides a method of forming an apparatus for forming a tissue array in an at least substantially solid recipient. The method includes providing an extractor member. The extractor member includes a stylus. The extractor member also includes a tubular end portion for accommodating a tissue sample. The tubular end portion has an opening. The method also includes providing a punch member. The punch member includes a stylus. The punch member also includes a tubular end portion for accommodating matter punched from the recipient. The tubular end portion has an opening. The method further includes providing a housing. The method also includes providing a first guiding means. Further the method includes arranging the first guiding means inside the housing. Thereby the stylus of the extractor member is arranged relative to the first guiding means to allow the first guiding means to provide fixation to the stylus inside the housing. As a result the stylus of the extractor member is movable in the axial direction. The method further includes providing a second guiding means. The method also includes arranging the second guiding means in the housing. Thereby the stylus of the punch member is arranged relative to the second guiding means to allow the second guiding means to provide fixation to the stylus of the punch member inside the housing. As a result the stylus of the punch member is movable in the axial direction. Further, the method includes providing a punch actuator. The punch actuator is arranged in such a way that it is in communication with the punch member. The method also includes providing an extractor actuator. The extractor actuator is arranged in such a way that it is in communication with the extractor member.

[0009] According to a third aspect, the invention provides a method of forming a tissue array. The method includes providing an apparatus according to the first aspect. The method also includes bringing the apparatus into a position where the opening of the tubular end portion of the extractor member is arranged about a tissue. Further, the method includes moving the tubular end portion of the extractor member in the direction defined by the orientation of the opening of the tubular end portion thereof. Thereby the tubular end portion of the extractor member is inserted into the tissue. The method further includes moving the stylus of the extractor member in the direction opposite to the opening of the tubular end portion of the extractor member. As a result a tissue sample is accommodated in the tubular end portion of the extractor member. The method also includes bringing the apparatus into a position where the opening of the tubular end portion of the punch member is in contact with an at least substantially solid recipient. The method further includes moving the stylus of the punch member in the direction defined by the orientation of the opening of the tubular end portion thereof. Thereby the tubular end portion of the punch member is inserted into the recipient. As a result a portion of the recipient is accommodated in the tubular end portion of the punch member and a cavity is formed in the recipient. The method further includes bringing the apparatus into a position where the opening of the tubular end portion of the extractor member is positioned about the cavity, generally on a top of the cavity, which has been formed in the recipient. The apparatus is positioned in such a way about the cavity formed in the recipient that the tissue sample accommodated in the tubular end portion of the extractor member can be inserted into the cavity. The method further includes releasing the tissue sample accommodated in the tubular end portion of the extractor member from the same. Thereby the tissue sample is inserted into the cavity formed in the recipient. [0010] According to a fourth aspect the invention provides a kit for forming a tissue array. The kit includes an apparatus according to the first aspect and an at least substantially solid recipient. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The invention will be better understood with reference to the detailed description when considered in conjunction with the non-limiting examples and the accompanying drawings. [0012] Figure 1 depicts two exemplary embodiments of a portable apparatus according to the invention. In the apparatus shown in Fig. IA a stylus (1) of a punch member and a stylus (2) of an extractor member are slightly inclined relative to each other. 41: opening of the tubular end portion of the punch member; 42: opening of the tubular end portion of the extractor member; 10: automated depth device; 3: punch actuator; 4 extractor actuator; 31: plate. Figure IB shows an apparatus in which a stylus (1) of a punch member and a stylus (2) of an extractor member are arranged parallel to each other. 41 : opening of the tubular end portion of the punch member; 42: opening of the tubular end portion of the extractor member; 50: housing; 10: automated depth device; 3: punch actuator; 4 extractor actuator; 14: handhold; 65, 66: ports; 51: lid. [0013] Figure 2 depicts a further embodiment of an apparatus according to the invention, which includes a punch member (6) to which a punch actuator (3) is coupled. 11 : tubular end portion of the punch member; 41: opening. An extractor actuator (4) is coupled to an extractor member (7). 21: tubular end portion of the extractor member; 42: opening; 8: punch bar; 9: an extractor bar; 14: grip; 13: plate structure. [0014] Figure 3 depicts a further embodiment of an apparatus according to the invention,

13: plate structure; 14: handle; 1: stylus of the punch member; punch holder (5); 2: stylus of the punch member; 11: tubular end portion of the punch member; 41: opening; 21: tubular end portion of the extractor member; 42: opening; 9: extractor bar; 8: punch bar; 4: extractor actuator; 3 : punch actuator. [0015] Figure 4 depicts the parts of the assembled apparatus: 14: grip; 13: plate structure;

4: extractor actuator; 3: punch actuator; 9: extractor bar; 8: punch bar; 19: housing; 6: punch member; 7: extractor member; 22: rubber; 23: rod of the punch member; 24: rubber; 25: rod of the extractor member; 26: end portion of the rod; 27: connector; 98: suction piston; 21 : tubular end portion of the extractor member; 42: opening; 11: tubular end portion of the punch member; 16: wire springs; 17: coil spring; 18: recipient remover.

[0016] Figure 5 shows the plate structure (13) before being assembled into the apparatus of the invention. 14: hand grip side; 33: assembly holes; 32: adjustment hole. [0017] Figure 6 depicts the housing (19) that has two guiding means in the form of hollow cylinders (40, 50) to provide guidance to the stylus of the punch member and the stylus of the extractor member. Cylinder (50) serves in guiding the punch to create a hole in the recipient. Cylinder (40) serves in guiding the stylus of the extractor member to collect and deliver tissue.

[0018] Figure 7 is a partial magnification of the punch member. 23: rod; 22: rubber; 19: housing; 47: punch container; 11: tubular end portion of the punch member; 42: opening: 18: recipient remover; 17: coil spring; 16: wire springs.

[0019] Figure 8 depicts an embodiment of the tubular end portion of the punch member. 35: handle.

[0020] Figure 9 depicts a paraffin remover. 36: handle.

[0021] Figure 10 is an enlarged view of the extractor member. 24: rubber; 25: rod of the extractor member; 26: end portion of the rod; 27: connector; 98: suction piston; 21 : tubular end portion of the extractor member; 42: opening. [0022] Figure 11 depicts an embodiment of the tubular end portion of the extractor member.

[0023] Figure 12 depicts a suction piston. 99: rubber.

[0024] Figure 13 is a schematic of a snap mechanism that may be used to secure the punch actuator and/or the extractor actuator by means of geometric fit. [0025] Figure 14 is an enlarged view showing the punch actuator (3) and the extractor actuator (4). 8: punch bar; 3: punch actuator; 9: extractor bar; 4: extractor actuator.

[0026] Figure 15 depicts a lever mechanism providing communication between the punch member and the extractor member. Fig. 15 A depicts a bar (108), a fulcrum (54), a ball- shaped recess (55) and a ball-shaped fulcrum (54). Fig. 15 B further depicts an extractor actuator (3) and a punch actuator (4).

[0027] Figure 16 depicts an embodiment of a method of the invention. 15: stylus of the extractor member; 102: tubular end portion; 42: opening; 1 : stylus of the punch member; 100:

- tissue; 110: tissue sample; 101: recipient; 111: punched recipient portion, 12: cavity. A: positioning the apparatus. B: The tubular end portion of the extractor member (102) is inserted into the tissue (100). C: A tissue sample (110) is collected. D, E: repositioning the apparatus.

F: Adjusting the position of the stylus (15) of the extractor member. G: The opening of the tubular end portion of the stylus (1) of the punch member is brought in contact with the recipient (101). H: Inserting the tubular end portion of the punch member into the recipient. I: Collecting a portion (111) of the recipient. J, K: repositioning the apparatus. L: releasing the tissue sample (110).

[0028] Figure 17 depicts a further embodiment of a method of the invention. 54: fulcrum; 108: bar; 1: stylus of the punch member; 15: stylus of the extractor member; 94, 95: guiding means; 19: housing; 96: spacer; 102: tubular end portion; 41, 42: opening; 100: tissue;

110: tissue sample; 101 : recipient; 111 : punched recipient portion, 12: cavity, 69: recipient portion reservoir. A: positioning the apparatus. B, C: inserting the tubular end portion of the extractor member (102) into the tissue (100). D: collecting a tissue sample (110). E, F: repositioning the apparatus. G: Inserting the tubular end portion of the punch member into the recipient. H: Collecting a portion (111) of the recipient. I: repositioning the apparatus; J: releasing the tissue sample (110); K: repositioning the apparatus. L,M: releasing the portion

(111) of the recipient.

[0029] Figure 18 depicts a further embodiment of a method of the invention. 54: fulcrum; 108: bar; 1: stylus of the punch member; 15: stylus of the extractor member; 94, 95: guiding means; 19: housing; 96: spacer; 102: tubular end portion; 41, 42: opening; 100: tissue;

110: tissue sample; 101: recipient; 111: punched recipient portion, 12: cavity, 69: recipient portion reservoir. A: positioning the apparatus. B, C: inserting the tubular end portion of the extractor member (102) into the tissue (100). D: collecting a tissue sample (110). E: repositioning the apparatus. F: releasing the communication between the two styli (1,15). G: repositioning the apparatus. H: Inserting the tubular end portion of the punch member into the recipient. I: Collecting a portion (111) of the recipient. J: repositioning the apparatus; K: releasing the tissue sample (110).

[0030] Figure 19 depicts a further embodiment of a method of the invention. 1: stylus of the punch member; 2: stylus of the extractor member; 41, 42: opening; 100: tissue; 110: tissue sample; 101: recipient; 111: punched recipient portion, 12: cavity. A: positioning the apparatus. B: inserting the tubular end portion of the stylus (2) of the extractor member into the tissue (100). C: collecting a tissue sample (110). D, E: repositioning the apparatus. F: inserting the tubular end portion of the stylus (1) of the punch member into the recipient. G: Collecting a portion (111) of the recipient. H,I: repositioning the apparatus; J: releasing the tissue sample (110).

[0031] Figure 20 depicts a further embodiment of a method of the invention. 1: stylus of the punch member; 2: stylus of the extractor member; 12: cavity; 41, 42: opening; 100: tissue; 110: tissue sample; 101: recipient; 111: punched recipient portion; 69: recipient portion reservoir. A: positioning the apparatus. B: inserting the tubular end portion of the stylus (2) of the extractor member into the tissue (100). C: collecting a tissue sample (110). D, E: repositioning the apparatus. F, G: inserting the tubular end portion of the stylus (1) of the punch member into the recipient. H: collecting a portion (111) of the recipient. I: repositioning the apparatus; J: moving only the extractor member; K: repositioning the apparatus; L, M: releasing the tissue sample (110); N: repositioning the apparatus. O,P: releasing the portion (111) of the recipient.

[0032] Figure 21 depicts a rotation mechanism (A) for rotating the stylus of the punch member, with a cross-section of stylus of the punch member (B). 44: spiral spring; 45: handle; 43: stylus.

[0033] Figure 22 depicts the apparatus of the invention contained in a suitcase. 50: apparatus; 57: suitcase; 58: recipient; 59: stage; 56: slider; 63: LCD; 64: control panel.

[0034] Figure 23 depicts an adhesive grid that may be positioned and optionally immobilised on the recipient.

[0035] Figure 24 depicts positioning the adhesive grid (75) on a recipient (101). 73: tissue holder; 74: recipient holder.

[0036] Figure 25 depicts a further arrangement of an apparatus of the invention contained in a suitcase. 73: tissue holder; 74: recipient holder; 76: light; 77: cover; 78: light cover resting bay; 79: bay for adhesive tape with grid; 83: drawer for tissue holder; 84: drawer: refill for the apparatus of the invention, 85: base, 86: foldable holder for the apparatus of the invention; 87: bay for tissue paper; 88: bay for cleaning solution; 89: handle.

[0037] Figure 26 depicts the arrangement of Fig. 25 in top view. 73: tissue holder; 74: recipient holder; 78: light cover resting bay; 79: bay for adhesive tape with grid; 83: drawer for tissue holder; 84: drawer: refill for the apparatus of the invention; 87: bay for tissue paper; 88: bay for cleaning solution; 93 : bay for the apparatus of the invention and for a foldable holder therefore.

[0038] Figure 27 briefly illustrates a further embodiment of a method of the invention. 1: stylus of the punch member; 2: stylus of the extractor member; 3: punch actuator 4: extractor actuator; 100: tissue; 110: tissue sample; 101: recipient; 111: punched recipient portion. A: inserting the tubular end portion of the stylus of the extractor member into the tissue (100). B: inserting the tubular end portion of the stylus of the punch member into the recipient. C: releasing the tissue sample (110); D: releasing the portion (111) of the recipient. DETAILED DESCRIPTION OF THE INVENTION

[0039] An apparatus according to the invention is designed for the formation of a tissue array, in particular a micro-tissue array. A tissue array and in particular a micro-tissue array includes a plurality of tissue samples. A respective tissue may be any tissue, for example a tissue obtainable or obtained from an organism, such as an animal, e.g. a mammalian species, including a rodent species, an amphibian, e.g. of the subclass Lissamphibia that includes e.g. frogs, toads, salamanders or newts, an invertebrate species, or a plant. Examples of mammals include, but are not limited to, a rat, a mouse, a rabbit, a guinea pig, a squirrel, a hamster, a hedgehog, a platypus, an American pika, an armadillo, a dog, a lemur, a goat, a pig, an opossum, a horse, an elephant, a bat, a woodchuck, an orang-utan, a rhesus monkey, a woolly monkey, a macaque, a chimpanzee, a tamarin (saguinus oedipus), a marmoset or a human. An illustrative example of a tissue is an organ or a portion thereof, such as adrenal, bone, bladder, brain, cartilage, colon, eye, heart, kidney, liver, lung, muscle, nerve, ovary, pancreas, prostate, skin, small intestine, spleen, stomach, testicular, thymus, tumour, vascular or uterus tissue, or connective tissue. The tissue may also be a tissue portion such as a tissue slice or an engineered tissue construct, hi some embodiments a tissue portion is used that has been obtained from a patient.

[0040] A tissue micro array typically serves as a validation and discovery platform that allows a rapid in situ analysis such as gene expression or cellular or tissue effects of one or more compounds of interest. The tissue samples of the array may be analysed independently from each other as well as in parallel. A tissue micro array may for instance be used in diagnosis, quality control or in screening techniques, including high throughput screening. Thereby data can be obtained in the context of in situ morphology. Hundreds and thousands or more of tissue samples may be arranged into a tissue array, usually in a recipient such as paraffin. The recipient that may be employed in the present invention is at least substantially solid and malleable to a degree that a cavity can be formed therein by means of mechanical punching. Furthermore the recipient is of a sufficient rigidity to be capable of retaining its shape after being deformed by mechanical punching. The recipient may for instance include or be a metal such as lead or a polymer such as rubber or low density polyethylene, or a wax such as paraffin. Analysis time and reagent amounts are drastically reduced when using a tissue array, and they are further reduced by the use of a micro array. Tissue samples of a micro array sample in the context of the present invention may be of a maximal width in the plane of the recipient surface that accommodates the tissue samples, which is in the mm range, i.e. about 1 to about 100 mm, the sub-millimeter range, i.e. about 0.1 to about 1 mm or below. The width of a tissue sample may for example be in the range from about 0.01 to about 10 mm, such as about 0.05 to about 5 mm or about 0.1 to about 2 mm. A typical tissue sample used in the art, also termed "core" in the art, is of a width of one of 0.6 mm, 1.0 mm, 1.5 mm or 2.0 mm. Thus only small tissue samples are taken from a donor tissue or donor tissue portion, which allows using the same plurality of tissues or tissue portions in the preparation of numerous tissue arrays, which may be different or identical. Exemplary introductions into the use of a tissue array in the field of cancer have for instance been given by Milanes-Yearsley et al. {Modern Pathology [2002] 15, 12, 1366-1373) or Zhang et al. (Modern Pathology [2003] 16, 1, 79-84).

[0041] The apparatus according to the invention includes an extractor member and a punch member. The extractor member serves in collecting a tissue sample as defined above while the punch member serves in forming a cavity in the recipient. The cavity can then accommodate the tissue sample collected by means of the extractor member. The same apparatus can thus be used repeatedly to collect and deposit samples, thereby forming a tissue array, typically in a single recipient. [0042] The extractor member includes a stylus. This stylus is at least substantially straight and free of curves, kinks, loops or bends. Thus stylus defines a linear axis along its length, which is generally a central axis. The extractor member may include other portions of any desired geometry such as a rod, a cuboid or a ball shaped portion. The stylus may define any desired portion of the extractor member. The length of the stylus may for instance stretch across the entire dimension of the extractor member defined by the axis of the stylus, or it may stretch across about 80 %, about 60%, about 50 %, about 40 %, about 30 % or about 20 % of the respective dimension.

[0043] The extractor member furthermore has a tubular end portion. The tubular end portion may for example have the shape of a cylinder. In some embodiments one end of the extractor member is defined by the stylus. This end of the extractor member serves in contacting and penetrating the tissue or tissue portion when collecting a tissue sample. Further, at this end of the extractor member the stylus has in such embodiments a tubular end portion. Accordingly, the tubular end portion of the extractor member is in these embodiments included in the stylus, hi some embodiments the stylus of the extractor member and the tubular end portion of the extractor member are securely mounted, such that they define one physical unit. In some of these embodiments the tubular end portion of the extractor member is dismountable from the stylus of the extractor member.

[0044] In some embodiments the tubular end portion of the extractor member is capable of accommodating the stylus of the extractor member. The stylus may for example be movable within the tubular end portion of the extractor member. The outer width of stylus and the inner width of the tubular end portion of the extractor member may in some of these embodiments be matched in such a way that moving the stylus within the tubular end portion of the extractor member can cerate a positive or negative pressure, depending on the direction of the movement, if the opening of the tubular end portion is blocked. In such embodiments the tubular end portion of the extractor member may be arranged in a fixed position relative to the residual apparatus. It may for instance be connected to the housing that includes guiding means for the styli. Thus, in such embodiments the tubular end portion of the extractor member is not movable in the axial direction of the extractor member stylus.

[0045] In some embodiments the tubular end portion of the extractor member is rotatable. In some embodiments the stylus of the extractor member is rotatable. In some embodiments both the stylus and the tubular end portion are rotatable. The explanations below for the punch member in this regard apply mutatis mutandis to the extractor member. Rotating the tubular end portion of the extractor member, in some embodiments together with the stylus of the extractor member, may assist in collecting a tissue sample. In embodiments where a relatively hard or frozen tissue is used, drilling may be required to penetrate the tissue and to collect a sample there from. A rotation of the tubular end portion of the extractor member may serve this purpose. [0046] In some embodiments the tubular end portion of the extractor member is removable, e.g. by means of a thread, hi some embodiments the stylus of the extractor member includes a stylus end portion that is removable. The stylus end portion may be securely mounted to the residual stylus of the extractor member, such that they define one physical unit. In some of these embodiments the stylus end portion of the extractor member is dismountable from the residual stylus of the extractor member. Exchanging the stylus end portion may be desired in order to adapt the apparatus to different requirements in terms of width and height of a tissue sample. Thus the stylus end portion may be replaced by another a stylus end portion, which has a larger or smaller width and/or a larger or smaller length in the axial direction. In some embodiments this stylus end portion is or includes the tubular end portion of the extractor member.

[0047] As indicated above, the tubular end portion of the extractor member has furthermore an opening. In some embodiments in the apparatus the opening of the end portion of the extractor member is in fluid communication with the ambience. In some embodiments fluid communication with the ambience can be provided and/or terminated, for instance my means of a closing device. Two illustrative examples of such a closing device are a lid and a valve. The closing device, e.g. lid, may for instance be coupled to a controller, which may be operated manually or in an automated way. Accordingly, in some embodiments the opening of the tubular end portion of the extractor member is accessible from the ambience. In some embodiments where the tubular end portion of the extractor member is included in the stylus of the extractor member at least a part of the tubular end portion is accessible from the ambience. In some embodiments the opening and/or at least a part of the tubular end portion of the extractor member become(s) accessible from the ambience once the stylus of the extractor member is moved in the direction defined by this opening of the tubular end portion of the extractor member.

[0048] The opening of the tubular end portion may be of any desired shape and orientation. It may for example be at least substantially circular, ovoid, semi-circular, triangular, rectangular, square shape, the shape of e.g. letters V or U, or of the shape of any polyhedron. The opening is further girded by an edge. The edge may be arranged in any desired plane relative to the axis defined by the stylus of the extractor member. In some embodiments the edge is arranged in a plane that is inclined more than about 45 ° with regard to the axis defined by the stylus of the extractor member, for example more than about 60 °, more than about 70 °, more than about 80 ° or more than about 85 °. In some embodiments the edge is arranged in a plane that is at least substantially perpendicular to the axis defined by the length of the stylus. The edge may — just as the opening itself- be of any shape. In embodiments where the edge is arranged in a plane that is perpendicular to the axis defined by the length of the stylus the shape of the edge and the shape of the opening are usually identical.

[0049] This edge that surrounds the opening of the tubular end portion of the extractor member serves in penetrating tissue. Upon penetration of tissue a tissue sample is formed, which enters the tubular end portion of the extractor member. For this purpose it is typically required that the tubular end portion is capable of accommodating a tissue sample punched by the edge. Besides this requirement the circumferential inner wall of the tubular end portion of the extractor member may be of any internal surface characteristics. The internal surface of the tubular end portion, or portions thereof, may thus for example be rendered water-attracting, typically polar, e.g. hydrophilic, or water-repellent, typically non-polar, e.g. hydrophobic. Different internal areas of the tubular end portion may also provide different surface characteristics. Thus, some inner wall-portions of the tubular end portion may be rendered polar, while others areas may be rendered non-polar.

[0050] A treatment of the internal surface of the tubular end portion that achieves an alteration of surface characteristics may be any treatment that leads to an alteration of the respective surface characteristics that lasts long enough for a subsequent collection of a tissue sample to be affected. Typically, this treatment does not affect the composition of a tissue sample contacting the respective surface area. In some embodiments the treatment does not affect the composition of any tissue or fluid that contacts the respective surface area. A treatment that may be carried out to alter surface characteristics may comprise various means, such as mechanical, thermal, electrical or chemical means. A method that is commonly used in the art is a treatment with chemicals having different levels of affinity for the fluid sample. As an example, the surface of plastic materials can be rendered hydrophilic via treatment with dilute hydrochloric acid or dilute nitric acid. As another example, a polydimethylsiloxane (PDMS) surface can be rendered hydrophilic by an oxidation with oxygen or air plasma. Alternatively, the surface properties of any hydrophobic surface can be rendered more hydrophilic by coating with a hydrophilic polymer or by treatment with surfactants. Examples of a chemical surface treatment include, but are not limited to exposure to hexamethyldisila- zane, trimethylchlorosilane, dimethyldichlorosilane, propyltrichlorosilane, tetraethoxysilane, glycidoxypropyltrimethoxy silane, 3-aminopropyltriethoxysilane, 2-(3,4-epoxy cyclohexyl)- ethyltrimethoxysilane, 3-(2,3-epoxy propoxyl)propyltrimethoxysilane, polydimethylsiloxane (PDMS), γ-(3,4-epoxycyclohexyl)ethyltrimethoxysilane, poly (methyl methacrylate), a poly- methacrylate co-polymer, urethane, polyurethane, fluoropolyacrylate, poly(methoxy polyethy- lene glycol methacrylate), poly(dimethyl acrylamide), poly[N-(2-hydroxypropyl)methacryl- amide] (PHPMA), α-phosphorylcholine-o-(N,N-diethyldithiocarbamyl)undecyl oligoDMAAm- oligo-STblock co-oligomer (see Matsuda, T et al., Biomaterials (2003), 24, 24, 4517-4527), poly(3 ,4-epoxy- 1 -butene), 3 ,4-epoxy-cyclohexylmethylmethacrylate, 2,2-bis[4-(2,3 -epoxy propoxy) phenyl] propane, 3,4-epoxy-cyclohexylmethylacrylate, (3',4'-epoxycyclohexyl- methyl)-3,4-epoxycyclohexyl carboxylate, di-(3,4-epoxycyclohexylmethyl)adipate, bisphenol A (2,2-bis-(p-(2,3 -epoxy propoxy) phenyl) propane) or 2,3 -epoxy- 1-propanol.

[0051] The stylus and the tubular end portion of the extractor member, as well as the stylus and the tubular end portion of the punch member may include or be of any solid material as long as the material is of a stability and stiffness that provides the solid with the capability of punching a tissue or recipient, respectively. Further, the stylus and the tubular end portion of the extractor member as well as the stylus and the tubular end portion of the punch member, are of a rigidity and stability that allows them to remain at least essentially intact during the operation of forming a tissue array. The stylus and/or the tubular end portion of both members may for instance include or consist of a metal or a metal alloy (e.g. stainless steel or titanium), a metalloid, ceramics, a metal oxide, a metalloid oxide, oxide ceramics, a polymer and composites thereof. A respective polymer may for example be or include plastic (such as thermoplastics) and include an elastomer (such as PDMS or elastic silicone rubber). Examples of suitable metalloids include, but are not limited to silicon, boron, germanium, antimony and composites thereof. Examples of suitable metals include, but are not limited to iron (e.g. steel), aluminium, gold, silver, chromium, tin, copper, titanium, zinc, aluminium, lead and composites thereof. A respective oxide of any of these metalloids and metals may be used as a metalloid oxide or metal oxide respectively.

[0052] As noted above, the apparatus of the invention is in some embodiments an apparatus for taking tissue samples in the millimetre range or below. The apparatus is in some embodiments an apparatus for forming a micro tissue array. Accordingly, the end portion of the the extractor member is in some embodiments designed to be capable of forming tissue samples with a maximal width in the selected range or with the selected value (see above). In some embodiments the edge of the tubular end portion of the extractor member has a maximal width of about 10 mm or below, of about 5 mm or below or about 2 mm or below.

[0053] In some embodiments the extractor member can be adapted to be capable of providing tissue samples with a desired maximal width. For this purpose, as well as any other purpose such as maintenance, any part of the extractor member, including the entire extractor member may be removable from the apparatus. In some embodiments the stylus and/or the tubular end portion of the extractor member is removable (see below). In one embodiment the tubular end portion included in the stylus is removable. As noted above, in some embodiments the stylus of the extractor member includes a stylus end portion that is removable. In some embodiments the stylus includes a suction piston (see e.g. Fig. 4) that can be accommodated by the tubular end portion of the extractor member. In such embodiments both the suction piston and the tubular end portion of the extractor member may be removable.

[0054] In some embodiments the tubular end portion of the extractor member has a thermostatic device or a Peltier heater incorporated therein to influence the temperature at which a tissue sample is accommodated inside the tubular end portion and/or to assist in collecting a tissue sample by creating a temperature gradient in the tissue. In this regard, the thermostatic device or Peltier heater may act a heating means, a cooling means or both.

[0055] As mentioned above, the punch member also includes a stylus. In some embodiments this stylus includes the tubular end portion of the punch member and includes an opening. In embodiments where the tubular end portion of the punch member is included in the stylus of the punch member, the respective tubular end portion defines a tubular end portion of the stylus. The above said with regard to dimensions, shape, edge, surface characteristics and opening applies mutatis mutandis also to the stylus and the tubular end portion of the punch member. In this regard the tubular end portion of the punch member is typically capable of accommodating matter punched by the corresponding edge from the recipient. The opening at the tubular end portion of the punch member is in some embodiments in fluid communication with the ambience. As described above for the extractor member, fluid communication with the ambience can in some embodiments be provided and/or terminated, and in some embodiments the opening of the tubular end portion of the stylus of the punch member is accessible from the ambience. Likewise, in some embodiments at least a part of the tubular end portion of the stylus of the punch member is accessible or may become accessible from the ambience. In some embodiments the edge of the tubular end portion of the stylus of the extractor member and the edge of the tubular end portion of the stylus of the punch member are of at least substantially identical shape. [0056] As explained above, the apparatus is in some embodiments an apparatus for forming a micro tissue array, and in some embodiments the extractor member can be adapted to be capable of providing tissue samples with a desired maximal width. In order to be able to provide corresponding cavities in the recipient for a selected width of a tissue sample, as well as any other purpose such as maintenance, any part of the punch member, including the entire punch member may be removable from the apparatus. In some embodiments the stylus of the punch member is removable. In one embodiment the tubular end portion of the punch member is removable. In typical embodiments the stylus of the punch member and the tubular end portion of the punch member are securely mounted, such that they define one physical unit. In some of these embodiments the tubular end portion of the punch member is dismountable from the stylus of the punch member. Exchanging the end portion of the punch member may be desired in order to adapt the apparatus to different requirements in terms of width and height of a tissue sample. Typically it will be desired to make use of the capability of the apparatus of the invention to match the width and height of a cavity formed in the recipient to the width and height of a tissue sample. For this purpose it will usually be required to replace the end portion of the punch member by another end portion with matching dimensions to a new tubular end portion of the extractor member, once the latter is being exchanged. Thus, similar to the end portion of the extractor member, the tubular end portion of the punch member may be replaced by another tubular end portion of the punch member, which has a larger or smaller width and/or a larger or smaller length in the axial direction. In embodiments where the tubular end portion of the punch member is included in the stylus of the punch member a stylus end portion, which includes the tubular end portion, may be replaced by another a stylus end portion, which has a larger or smaller width and/or a larger or smaller length in the axial direction. When exchanging the tubular end portion of the punch member in order to provide matching dimensions between the tubular end portions of punch and extractor member it should be observed that a cavity with matching dimensions for a selected tissue sample is obtained when the outer width (e.g. diameter) of the tubular end portion of the punch member matches the inner width (e.g. diameter) of the tubular end portion of the extractor member.

[0057] In some embodiments the tubular end portion of the punch member is rotatable. In some embodiments the stylus of the punch member is rotatable. In some embodiments both the stylus and the tubular end portion are rotatable. As noted above, in typical embodiments the stylus of the punch member includes the tubular end portion of the punch member. Accordingly, in some embodiments the stylus of the punch member is rotatable together with the tubular end portion of the punch member. In some embodiments the stylus of the punch member has an end portion that includes the tubular end portion of the punch member (supra). In such embodiments the end portion of the stylus of the punch member may be rotatable together with the tubular end portion of the punch member. The punch member may for example include means to rotate the stylus and/or the tubular end portion, such as a handle for manual actuation, coupled to the stylus/ tubular end portion, a motor, or a spring mechanism. Thereby a twisting mechanism may be provided that may be applied during the process of punching a cavity into a recipient. For this purpose a leaf spring may be coupled, e.g. affixed, to the stylus and/or the tubular end portion of the punch member. Such a mechanism allows twisting the cut-off recipient portion, e.g. paraffin, so as to result in the formation of a smooth cavity, e.g. hole. Punching without twisting may result in the punched portion of the recipient not being able to leave the residual recipient. An illustration of a respective twisting mechanism is shown in Figure 21.

[0058] The apparatus also includes a housing. The housing may be of any desired size and geometry as long as it can be accommodated by the apparatus and is capable of including two guiding means (see below). Similar to the stylus of the extractor member and the stylus of the punch member the housing may be of any size and geometry and include any matter as long as the housing remains at least essentially intact during the operation of collecting a tissue sample with the apparatus.

[0059] The housing includes a first guiding means and a second guiding means. The first guiding means serves in guiding the stylus of the extractor member and in providing fixation to the stylus of the extractor member inside the housing. The second guiding means serves in guiding the stylus of the punch member and in providing fixation to the stylus of the punch member inside the housing. The fixation provided by the first guiding means renders the stylus of the extractor member movable in the axial direction. Likewise, the fixation provided by the second guiding means is designed in such a way that the stylus of the punch member is movable in the axial direction. The first and the second guiding means are typically a geometrical element such as a rail, a groove, or a channel, for instance in the form of a hollow cylinder, or any combination thereof. This geometrical element may be included in the housing, e.g. as an integrated part thereof, or be arranged therein. In some embodiments one or both of the guiding means are at least partially encasing the stylus of the respective member, e.g. the second guiding means the stylus of the punch member. One or both of the guiding means may for instance have a circumferential wall that can accommodate the stylus of the respective member, such that the stylus is movable within this circumferential wall in the axial direction. Typically such a circumferential wall has an axis, which is parallel to or the same as the axis of the stylus. The two guiding means may be selected independently from each other. In some embodiments the first and the second guiding means are corresponding geometrical elements, e.g. tubes. In some embodiments the dimensions of the first and the second guiding means are at least substantially identical.

[0060] The two guiding means secure independently both the stylus of the extractor member and the stylus of the punch member in a fixed line of positions relative to the housing.

This line of positions is at least substantially parallel to the axis of each respective stylus, i.e. of the punch member or of the extractor member. Accordingly, the stylus of the extractor member is movable one-dimensionally at least substantially parallel to the axis defined by its length. Likewise, the stylus of the punch member is movable one-dimensionally at least substantially parallel to the axis defined by its length. Accordingly, each of the two styli is typically movable in the axial direction guided by the respective guiding means. It may during a movement in the axial direction move, including float, slide, glide, slip, skid or drift along, within or across the respective guiding means.

[0061] The stylus of the extractor member and the stylus of the punch member may be arranged in any desired orientation relative to each other, including offset, such as perpendicular, or at any angle between 0 and 360 °. hi some embodiments the two styli are arranged relative to each other with an inclination of about 20 ° or less or about 10 ° or less, e.g. of about 5 ° or less as shown in Fig. IA. In some embodiments the two styli are arranged at least substantially parallel to each other. Where herein reference is made to two styli that are arranged at least substantially parallel to each other, a relative inclination of about 10 ° or less is understood to be included in the respective reference/embodiment. In one embodiment the two styli are arranged at least substantially parallel to each other with the same orientation with respect to the opening of their styli. In this embodiment the stylus of the extractor member runs at least substantially parallel to the stylus of the punch member with the openings of both styli facing at least substantially the same direction.

[0062] The apparatus also includes a punch actuator and an extractor actuator. The punch actuator is in communication with, including coupled to the stylus of the punch member. The extractor actuator is in communication with, including coupled to the stylus of the extractor member. Both actuators can independently from one another be operated, for example by electrical, electromechanical, mechanical, magnetic, thermal, optical, hydraulic or pneumatic means or by a change of air pressure. Either actuator may for example operate via a change of its position, hi some embodiments the punch actuator is coupled to the stylus of the punch member in a manner that operation of the punch actuator into a first position is imparted to a movement of the stylus of the punch member in the direction of the opening of the tubular end portion of the punch member. As an illustrative example, the punch actuator may be a pushbutton. The first position may be a position in which the push-button is in an "up"-position, where it can be pushed down. The second position may be a "down"-position, where the pushbutton has been pressed down and where it can be released to move into the first position automatically or where it can be lifted into the first position. Likewise, in some embodiments the extractor actuator is coupled to the stylus of the extractor member in a manner that operation of the extractor actuator into a first position is imparted to a movement of the stylus of the extractor member in the direction of the opening of the tubular end portion of the extractor member. The above example applies mutatis mutandis here. [0063] The way in which the two actuators are operated may be different, similar or the same. As an illustrative example, the extractor actuator may in one embodiment be operated by electrical means, whereas the punch actuator may be operated by mechanical means. In some embodiments both actuators may be operated mechanically. In one embodiment the two actuators may for example be buttons that can manually be pressed and/or pulled. The respective actuator may for example be coupled to its member via a bar, a cord, a spring or any other device. Generally, operating the extractor actuator causes a movement of the stylus of the extractor member, and operating the punch actuator causes a movement of the stylus of the punch member. The punch actuator may for example be coupled to the stylus of the punch member in such a manner that operating the punch actuator effects a movement of the stylus of the punch member in the axial direction defined by the opening of the tubular end portion thereof. Likewise, the extractor actuator may be coupled to the stylus of the extractor member in such a manner that operating the extractor actuator effects a movement of the stylus of the extractor member in the axial direction defined by the opening of the tubular end portion thereof. The extractor actuator may also be coupled to the stylus of the extractor member in such a manner that operating the extractor actuator effects a movement of the stylus of the extractor member in the axial direction that is opposite to the opening of the tubular end portion thereof. Likewise, the punch actuator may also be coupled to the stylus of the punch member in such a manner that operating the extractor actuator effects a movement of the stylus of the punch member in the axial direction that is opposite to the opening of the tubular end portion thereof. In some embodiments the punch actuator is operatable in two dimensions or into two modes. One dimension or mode may effect a movement of the stylus of the punch member in the direction that defined by the opening of the tubular end portion thereof, whereas the other dimension or mode may effect a movement of the stylus of the punch member in the opposite direction. In some embodiments the extractor actuator is also operatable in two dimensions or into two modes. One dimension or mode may effect a movement of the stylus of the extractor member in the direction that defined by the opening of the tubular end portion thereof, whereas the other dimension or mode may effect a movement of the stylus of the extractor member in the opposite direction. [0064] In addition, operating the extractor actuator may also cause a movement of the stylus of the punch member and vice versa. In some embodiments a controller may control whether an actuator is operable, for example by arresting or releasing one or both of the actuators. As an illustrative example one or both of the actuators may be securable by a catch, which may be a releasable interlock. The catch may for instance be designed to secure the position of the respective actuator, for example by means of geometric fit.

[0065] In some embodiments the punch member is in unidirectional communication with the extractor member, for instance via the interaction of bars or of gear wheels. A socket and plug configuration may be utilized as well. As an illustrative example, a bar or a gear wheel that is part of or connected to the punch member may be able to engage a bar or a gear wheel of the extractor member upon movement in one direction. Movement of the punch member thus translates into movement of the extractor member. Upon movement in the opposite direction such bars or gear wheels may be moved apart and thus a bar or a gear wheel that is part of or connected to the punch member may not be able to engage a bar or a gear wheel of the extractor member. [0066] As explained above the stylus of the punch member is one-dimensionally movable in a first and in a second direction at least substantially parallel to the axis defined by the length of the stylus. The first direction is defined by the orientation of the opening of the tubular end portion of the punch member and the second direction is opposite thereto. Such a unidirectional communication may be provided via the punch actuator. Accordingly, the punch actuator may for instance cause the movement of bars or of gear wheels that are capable of interacting with bars or with gear wheels coupled to the stylus of the extractor member. As the communication is in some embodiments unidirectional, movement of the stylus of the punch member in one direction may be transferred into movement of the stylus of the extractor member, while movement of the stylus of the punch member in the other direction does not cause any movement of the stylus of the extractor member. In some embodiments the stylus of the punch member is in unidirectional communication with the stylus of the extractor member in the second direction (supra). Accordingly, movement of the stylus of the punch member in the second direction is imparted to the stylus of the extractor member, whereas movement of the stylus of the punch member in the first direction is not imparted to the stylus of the extractor member.

[0067] As noted above, in some embodiments the two styli, i.e. the stylus of the punch member and the stylus of the extractor member, are arranged at least substantially parallel to each other. Typically, in such embodiments the tubular end portions of the extractor member and the punch member are likewise arranged at least substantially parallel to each other. In some of these embodiments the unidirectional communication of the stylus of the punch member with the stylus of the extractor member is provided to cause one-dimensional movement of the stylus of the extractor member in at least substantially a direction that is parallel to the axis defined by the stylus of the punch member. In one embodiment this direction is opposite to the direction in which the punch member stylus is moved. In this embodiment the two styli may have opposite orientations relative to the tubular end portion of one member. The tubular end portions of the two members may be arranged in opposite directions relative to the styli. Thus, the tubular end portion of the extractor member may have an opening that points in the opposite direction when compared to the opening of the tubular end portion of the punch member. Likewise, one stylus may have an end portion that points in the opposite direction compared to an end portion of the other stylus. In one embodiment the two styli are arranged at least substantially parallel to each other with the same orientation with respect to the opening of their respective member. In this embodiment the two styli are in unidirectional communication in such a manner that unidirectional communication of the punch member with the extractor member is provided to cause one-dimensional movement of the two members in the respective axial directions that are at least substantially the same, including along at least substantially the same axis. This axis may be an axis that is parallel to the two styli. In this embodiment under the operation of unidirectional communication the two styli move at least substantially parallel to each other in at least substantially the same direction. This movement may be synchronous.

[0068] As an illustrative example, the apparatus may be designed in such a way that the openings of the two members, i.e. the opening of the tubular end portion of the punch member and the opening of the tubular end portion of the extractor member, point into the same direction. This direction is the direction into which the tubular end portion of the extractor member is moved in order to insert the same into a tissue. Due to the force of gravity the tissue will usually be arranged below the opening of the tubular end portion of the extractor member. For sake of convenience the apparatus will upon inserting the opening of the tubular end portion into the tissue often be held in a position, in which the stylus of the extractor member is moved in about the direction in which gravity attracts matter, i.e. parallel to the force of gravity. For the sake of clarity the direction into which the opening of the tubular end portion of the extractor member faces, or points, can thus also be termed "down". The opposite direction can thus be termed "up", and matter arranged in the opposite direction relative to the apparatus may also be taken to be arranged "on a top of, "on top of or "above" the apparatus. Using these relative terms, moving the stylus of the extractor member in the direction opposite to the orientation of the opening of the tubular end portion of the extractor member could be called moving the stylus upward. In some embodiments where the two styli are arranged parallel to each other, the opening of the tubular end portion of the punch member is also pointing downward, i.e. in the same direction as the opening of the tubular end portion of the extractor member, m such embodiments moving the stylus of the punch member in the direction opposite to the orientation of the opening of the tubular end portion of the punch member could also be called moving the stylus upward. In some embodiments the stylus of the punch member is in unidirectional communication with the stylus of the extractor member in such a way that moving the stylus of the punch member upward causes a movement of the stylus of the extractor member upward. Moving the stylus of the punch member downward, however, does not cause a movement of the stylus of the extractor member downward (cf. e.g. Fig. 14).

[0069] In some embodiments the stylus of the extractor member is in unidirectional communication with the stylus of the punch member in the direction defined by the orientation of the opening of the tubular end portion of the extractor member. Accordingly, movement of the stylus of the extractor member in the direction defined by the orientation of the respective opening is imparted to the punch member. Movement of the stylus of the extractor member in the opposite direction is however not imparted to the stylus of the punch member. Again, this communication may cause a movement of the stylus of the punch member in any direction. In some embodiments this unidirectional communication causes movement in a direction that is at least substantially parallel to the axis of the stylus of the extractor member. Similar to the unidirectional communication of the stylus of the punch member to the stylus of the extractor member, in one embodiment under the operation of unidirectional communication the two styli move at least substantially parallel to each other in at least substantially the same direction. [0070] Following the above example of terming the direction into which the opening of the tubular end portion of the extractor member faces, or points, downward, both styli may in some embodiments be arranged parallel to each other with the opening of the tubular end portion of the punch member also pointing downward. The stylus of the extractor member may in a respective example be in unidirectional communication with the stylus of the punch member in such a way that only a movement of the stylus of the extractor member downward is imparted to the stylus of the punch member. A movement of the stylus of the extractor member upward is accordingly not imparted to the stylus of the punch member.

[0071] In one embodiment the stylus of the punch member is in unidirectional communication with the stylus of the extractor member in the second direction (supra), whereas the stylus of the extractor member is in unidirectional communication with the stylus of the punch member in the first direction. As an illustrative example, operating the extractor actuator in one dimension may cause movement of both styli in the first direction. Operating the extractor actuator in another dimension may cause only movement of the stylus of the extractor member in the second direction. Further, operating the punch actuator in one dimension may cause movement of both styli in the second direction. Operating the punch actuator in another dimension may cause only movement of the stylus of the punch member in the first direction. Following the above example of using the terms "up" and "down" the two styli could be in unidirectional coupling in such a way that moving the stylus of the extractor member down causes a movement of the stylus of the punch member down and moving the stylus of the punch member up causes a movement of the stylus of the extractor member up. A movement in the respective opposite directions could in contrast thereto not be imparted to the other stylus. Hence, moving the stylus of the extractor member up would have no effect on the position of the stylus of the punch member and neither would moving the stylus of the punch member down have an effect on the position of the stylus of the extractor member. [0072] In some embodiments the stylus of the punch member is in communication with the stylus of the extractor member in a reciprocal relationship. This form of communication effects movements of the styli in opposite directions. Movement of the stylus of the punch member in the direction of the opening of the tubular end portion thereof effects movement of the stylus of the extractor member in the direction opposite to the opening of the tubular end portion of the extractor member and vice versa. As explained above, in some embodiments the two styli are arranged parallel to each other with the openings of the two members orientated in the same direction. Following the above example of using the terms "up" and "down" the two styli could be in communication in such a way that moving the stylus of the extractor member up causes a downward movement of the stylus of the punch member. Likewise, moving the stylus of the extractor member down may cause an upward movement of the stylus of the punch member. Further, moving the stylus of the punch member up may cause a downward movement of the stylus of the extractor member. Moving the stylus of the punch member down may cause an upward movement of the stylus of the extractor member. The two styli may for example define the two legs of a rocker or teeter board. They may or example be flexibly coupled to a common bar (cf. Fig. 17 and Fig. 18). In this example the bar and styli may further be rotatable around a fulcrum in both the plane defined by the styli and the bar as well as the plane perpendicular thereto. Rotating the bar around the fulcrum in the plane perpendicular to the plane defined by the styli (cf. Fig. 15, see Fig. 18F) may also provide a mechanism of revoking or releasing the communication between the two styli. Rotating the bar may for example move one of the styli into a position where it can be unhinged or otherwise released from the bar.

[0073] In this regard the terms "release" and "released" as used herein, refer to any action or mechanism abrogating, blocking, cancelling, countermanding or ending an existing communication, including coupling, between the two styli of the apparatus. Abrogating, cancelling, countermanding or ending an existing communication may be of a final nature or of a reversible nature. Accordingly, the term "releasable", as used herein, refers to an arrangement, generally a position, of a stylus, in which it is possible for a user to deliberately abrogate, block, cancel or end an existing communication with the other stylus. As an example, ending or blocking the communication between the two styli may be achieved by means of operating a mechanism that alters the position of one or both styli. A respective mechanism may be provided in the apparatus, e.g. in the form of an additional bar, cord or string that is capable of engaging one of the styli. Such an additional bar, cord or string may for instance be operated via an additional actuator. Typically the action or mechanism abrogating, blocking, cancelling or ending an existing communication between the styli involves a movement of at least one of the styli of the apparatus out of a position in which it is unidirectionally, reciprocally or otherwise in communication with the other stylus into a position where it is no longer in such communication with the other stylus. As an illustrative example, an additional bar used to provide communication, e.g. coupling, between the two styli may be disengaged from a stylus.

[0074] In some embodiments a unidirectional communication, e.g. a coupling of the two styli that operates in only one dimension, is releasable. As an illustrative example, the position of a bar or a gear wheel that is part of or connected to the punch member may be altered in such a way that it is no longer able to engage a bar or a gear wheel of the extractor member and vice versa. A respective change of position may for instance be achieved via a further bar, gear wheel, cord, or spring that is in communicating with the corresponding bar or a gear wheel that is part of or connected to the punch member or the extractor member. As indicated above, in some embodiments a communication, including a coupling, of the styli in a reciprocal relationship is also releasable.

[0075] In some embodiments the position of the stylus of the punch member can be secured, e.g. arrested, for example via a lock, a snap-fit or tight-fit means or by a socket and plug configuration. The stylus of the punch member may for example be in communication with or include an actuable lock. Such an actuable lock may be coupled to the punch member, for instance via a bar, gear wheel, cord, or spring. Actuation of the lock may block movement, including actuation, of the stylus of the punch member in one direction. This direction may for example be the direction opposite to the tubular end portion of the punch member, i.e. the second direction as defined above.

[0076] In some embodiments the apparatus is affixed to another device such as a control instrument, including a robot. In some embodiments the apparatus includes further devices such as a camera for monitoring the position of a stylus or of the opening of the extractor member. In some embodiments the tubular end portion of the extractor member is included in the stylus of the extractor member (supra). In such an embodiment a camera may be provided to monitor the position of the opening of the respective stylus of the extractor member, for instance relative to a tissue or tissue portion. As noted above the stylus of the punch member typically includes the tubular end portion of the punch member. Thus the stylus of the punch member also includes the opening thereof. In such embodiments a camera may also be provided for monitoring the position of the opening of the stylus of the punch member. In some embodiments the apparatus is portable. It may for example be a handheld device. It may in this regard include a grip, a handhold or surface characteristics, such as a surface texture or pattern, designed to assist in holding the apparatus in an operator's hand.

[0077] In some embodiments the stylus of the punch member is unidirectionally coupled to the stylus of the extractor member, and/or vice versa, such that movement of a defined distance of the stylus of the punch member is imparted to the stylus of the extractor member to cause movement by the same defined distance. Thus, unidirectional coupling the two styli has the effect that movement of the stylus of the punch member by a certain distance causes movement of the stylus of the extractor member by about the same distance. As explained above, this movement may be in at least substantially the same direction, hi embodiments where the stylus of the punch member is in communication with the stylus of the extractor member in a reciprocal relationship, this communication may also be arranged to cause movement of both styli by the same defined distance. In embodiments where the two styli are coupled to a bar, which is pivotable at a fulcrum in the plane defined by the two styli, this may be achieved by designing the bar that brings the two styli in communication in such a way that the distance from the fulcrum to both styli is the same.

[0078] hi some embodiments the maximal inner width of the tubular end portion of the extractor member and the outer width of the tubular end portion of the punch member are matched. Such coordination of the respective widths, e.g. diameters, may be taken with a view to form a cavity in the recipient that matches the width of the tissue sample taken. As an example, the maximal width of the tubular end portion of the extractor member, possibly including the opening thereof, may be selected to be smaller, including slightly smaller, than the minimal width of the tubular end portion of the extractor member. With such coordination the tissue sample will generally fit into the cavity formed by the punch member. The edge of the tubular end portion of the extractor member may accordingly have a maximal inner width that is at most of about the same size as the minimal outer width of the edge of the tubular end portion of the punch member, hi some embodiments the edge of the tubular end portion of the extractor member has a maximal inner width that is of about the same size as the minimal outer width of the edge of the tubular end portion of the punch member. With such coordination the tissue sample will generally still fit into the cavity formed by the tubular end portion of the punch member, at the same time leaving about the smallest void possible in the cavity, once it accommodates the tissue sample. In some embodiments the edge of the tubular end portion of the extractor member has a maximal inner width that is at most of about the same size as the maximal outer width of the edge of the tubular end portion of the punch member. In some embodiments the edge of the tubular end portion of the extractor member has a maximal inner width that is of about the same size as the maximal outer width of the edge of the tubular end portion of the punch member. In one embodiment both the edge of the tubular end portion of the extractor member and the edge of the tubular end portion of the punch member are of circular shape. In this case the inner width of the edge of the tubular end portion of the extractor member and the outer width of the edge of the tubular end portion of the punch member may be identical.

[0079] The present invention also provides a method of forming a tissue array, including a micro tissue array. In this regard, the invention also relates to the use of an apparatus as defined above in forming a tissue array, hi the method the apparatus of the invention may be brought into a position where the opening of the tubular end portion of the extractor member is in contact with a tissue. The tubular end portion of the extractor member is moved in the direction defined by the orientation of the opening of the tubular end portion thereof, thereby inserting the tubular end portion, or a selected portion thereof, into the tissue, hi some embodiments inserting the tubular end portion of the extractor member (or a selected portion thereof) into the tissue is carried out after the opening of the end portion of the stylus of the extractor member has been brought in contact with a tissue, albeit this may be carried out in the same uniform process. Inserting the tubular end portion of the extractor member into the tissue may be carried out by moving the extractor member independently from the residual apparatus, hi some embodiments inserting the tubular end portion of the extractor member into the tissue is achieved by moving the entire apparatus, including the tubular end portion of the extractor member, in the direction defined by the orientation of the opening of the tubular end portion of the extractor member. In some embodiments inserting the tubular end portion of the extractor member into the tissue is achieved by operating the extractor actuator. [0080] In some embodiments the stylus of the extractor member includes the tubular end portion of the extractor member or is connected therewith. Such embodiments may be particularly well suited for hard or frozen tissue. In such embodiments the tubular end portion is accordingly movable in the axial direction of the stylus of the extractor member. In such embodiments bringing the apparatus into a position where the opening of the tubular end portion of the extractor member is arranged about the tissue or where it is in contact with the tissue includes bringing the stylus of the extractor member into a predefined position in the direction defined by the orientation of the opening of the tubular end portion thereof. This position may be a position to which the stylus of the extractor member can be returned whenever desired, for instance by providing a lock, a stop member or a guide mechanism. In some embodiments this position is a stop position, such as a bedstop or a depth gauge that represents the maximal position into which the stylus of the extractor member may be moved in the direction defined by orientation of the tubular end portion thereof. From such a stop position the stylus of the extractor member can for example only be moved in the direction opposite to the direction defined by the orientation of its tubular end portion. In such embodiments inserting the stylus of the extractor member into the tissue needs to be carried out by moving either the entire apparatus or a portion thereof that encompasses the stylus of the extractor member - rather than only moving the stylus of the extractor member, for instance by operating the extractor actuator, while the residual apparatus remains in an unchanged position.

[0081] In some embodiments moving the stylus of the extractor member in the direction defined by the orientation of the tubular end portion thereof and thereby inserting a selected portion of the tubular end portion of the extractor member into the tissue may include operating at least one of the extractor actuator and the punch actuator. As an illustrative example, first the extractor actuator may be operated to move the stylus of the extractor member in a first direction. This first direction is defined by the orientation of the opening of the tubular end portion of the extractor member. Following the above example of using the terms "up" and "down", the stylus of the extractor member would be moved downward. By moving the stylus of the extractor member in this first direction a selected portion of the tubular end portion may be inserted into the tissue. Then the extractor actuator may again be operated to move the stylus of the extractor member in a second direction. This second direction is opposite to the direction defined by the orientation of the opening of the tubular end portion of the extractor member. This direction would be upward, following the above terminology (supra). Thereby the selected portion of the tubular end portion thereof may be moved out of the tissue.

[0082] Upon inserting the stylus of the extractor member into the tissue, a tissue sample is accommodated in the tubular end portion of the stylus of the extractor member. In order to obtain a tissue sample with a selected dimension in the axial direction of the tubular end portion of the extractor member a selected portion of the tubular end portion of the extractor member may be inserted into the tissue.

[0083] In some embodiments the stylus of the extractor member is a separate element from the tubular end portion of the extractor member. Tubular end portion and stylus of the extractor member may for instance be movable independent from one another. The tubular end portion of the extractor member may also be arrestable or fixed to one or more portions or elements of the apparatus such as the housing, whereas the stylus of the extractor member is allowed to freely move in its axial directions. The stylus of the extractor member may for example be movable within the tubular end portion of the extractor member. In such embodiments the stylus, but not the tubular end portion may accordingly be movable in the axial direction of the stylus of the extractor member. Similar to embodiments with a stylus that includes the tubular end portion of the extractor member (supra), bringing the apparatus into a position where the opening of the tubular end portion of the stylus of the extractor member is in contact with the tissue may include bringing the stylus of the extractor member into a predefined position such as e.g. a stop position.

[0084] As further explained below, in typical embodiments where the stylus of the extractor member is movable within the tubular end portion of the extractor member, the entire tubular end portion may be inserted into the tissue or tissue portion. Any desired portion of the tubular end portion of the extractor member may typically be inserted into the tissue. In some embodiments this portion is of the same or a larger width in the axial direction than the desired width of the tissue sample in the direction perpendicular to the surface of the recipient. In some embodiments it is merely required that the edge of the tubular end portion of the extractor member is in such contact with the tissue that the interior of the tubular end portion is hermetically sealed from the ambience (see below). Such embodiments are particularly well applicable for soft tissue.

[0085] Additional techniques such as a temperature difference to the tissue, vibration or rotation of the tubular end portion of the extractor member may be used to collect this tissue sample. After inserting a selected portion of the tubular end portion of the extractor member into the tissue in some embodiments the extractor member is moved in the direction opposite to the orientation of the tubular end portion thereof. Using the above terminology of "up" and "down" this movement would be upward. By this movement the tissue sample is being removed from the tissue. As noted above, in some embodiments the tubular end portion of the extractor member is connected to or part of the stylus of the extractor member. In such embodiments this stylus of the extractor member may be moved in the direction opposite to the orientation of the opening of the tubular end portion thereof until the tubular end portion, which may at the same time be the end portion of the stylus, emerges from the tissue, i.e. until the tubular end portion is no longer in contact with the tissue. The method may include monitoring the movement of the tubular end portion out of the tissue, for instance by means of optical monitoring or by means of a detector such as a photo sensor or by means of a camera. It may in particular be monitored whether the selected portion of the tubular end portion, being the end portion of the stylus, is still inserted into the tissue. Further, the method may include arresting the stylus of the extractor member relative to the residual apparatus as soon as the tubular end portion is no longer in contact with the tissue or no longer inserted into the tissue. [0086] In embodiments where the stylus of the extractor member includes the tubular end portion of the extractor member, removing the tissue sample from the tissue and accommodating the same in the tubular end portion of the extractor member may be assisted or accomplished by a securing device. In some embodiments maintaining the tissue sample within the tubular end portion of the extractor member may also be achieved by a securing device, which may be the same as the securing device used to remove the tissue sample from the tissue. Such a securing device may for example act mechanically or by providing a pressure difference. In the latter case a reduced pressure may be generated in the tubular end portion of the extractor member, resulting in a suction effect. As an illustrative example, a pole or pin (cf. Fig. 12) with a cross sectional profile may be arranged in the apparatus that corresponds to the cross sectional profile of the tubular end portion of the extractor member stylus. The outer maximal and minimal widths of the pole or pin may match the inner maximal and minimal widths of the tubular end portion of the stylus of the extractor member (cf. Fig. 11). Moving the pole or pin inside the tubular end portion of the extractor member, and along the axis of the same, create negative or positive pressure, respectively, once the opening of the stylus is blocked, e.g. by a tissue or tissue portion.

[0087] In some of the embodiments where the stylus of the extractor member is movable within the tubular end portion of the extractor member such movement of the stylus is employed to collect the tissue sample and to accommodate it in the tubular end portion of the extractor member. Moving the stylus of the extractor member in the direction opposite to the tubular end portion of the extractor member may accordingly include moving the stylus of the extractor member within the tubular end portion of the extractor member. The stylus of the extractor member may be moved within the respective tubular end portion in the direction opposite to the opening of the tubular end portion of the extractor member. It is recalled that at this stage the tubular end portion of the extractor member is inserted into the tissue. If the stylus has a width perpendicular to the axial direction that matches the width of the tubular end portion in the same plane the stylus can hermetically seal the tubular end portion of the extractor member in the axial direction opposite to the opening of the tubular end portion. The opening of the tubular end portion may be hermetically sealed by the tissue, in which the tubular end portion is inserted. Accordingly, moving the stylus within the tubular end portion generates in such embodiments a negative or a positive pressure.

[0088] Moving the stylus of the extractor member in the direction opposite to the tubular end portion of the extractor member may thus include generating a negative pressure in the tubular end portion, such that a tissue sample is drawn into the tubular end portion of the extractor member. Accordingly, regardless of the distance by which the tubular end portion has been inserted into the tissue, it is in such embodiments merely required that a negative pressure can be established within the tubular end portion relative to the ambience. As long as the consistency of the tissue allows being drawn into the tubular end portion of the extractor member, the width of the tissue sample in the axial direction of the tubular end portion of the extractor member is merely determined by the movement of the stylus in the tubular end portion. Tissue of the tissue sample typically is being drawn into the tubular end portion until the pressure in the tubular end portion is about the same as the pressure of the ambience. Hence, generally the distance between the tissue surface and the stylus of the extractor member is the same before and after moving the stylus of the extractor member. [0089] Moving the tubular end portion of the extractor member in the direction opposite to the orientation of the opening thereof may be achieved by moving the entire apparatus in the direction opposite to the orientation of the opening of the tubular end portion of the extractor member, e.g. upward. Thereby the apparatus, including the tubular end portion and the stylus of the extractor member, is typically lifted in embodiments where the tissue was arranged in the direction of gravity relative to the opening of the tubular end portion of the extractor member.

[0090] As explained above, in some embodiments the stylus of the punch member is in communication with the extractor member in a reciprocal relationship. In such embodiments this communication between the styli may be designed in such a way that movement of the stylus of the punch member in the direction of the opening of the tubular end portion thereof effects movement of the stylus of the extractor member in the direction opposite to the opening of the tubular end portion of the extractor member and vice versa (see above). After the tubular end portion of the extractor member has been inserted into the tissue, moving the stylus of the extractor member in the direction opposite to the orientation of the opening of the tubular end portion of the extractor member may in such embodiments be achieved by moving the stylus of the punch member in the direction of the opening of the tubular end portion of the same. Following the above example of terming the direction into which the opening of the extractor member faces, or points, downward, both styli may be arranged parallel to each other with the opening of the punch member also pointing downward. After the tubular end portion of the extractor member has been inserted downward into the tissue, the stylus of the extractor member may be moved upward out of the tissue. This may be achieved via the reciprocal communication of the two styli. Moving the stylus of the extractor member upward causes a downward movement of the stylus of the punch member and vice versa. Moving the stylus of the extractor member upward can be achieved by moving the stylus of the punch member upward.

[0091] As already explained above, in some embodiments of the apparatus of the invention the stylus of the punch member of the apparatus is one-dimensionally movable in a first and in a second direction at least substantially parallel to the axis defined by the length thereof. The first direction is defined by the orientation of the opening of the tubular end portion of the punch member and the second direction is opposite thereto (supra). The stylus of the punch member may be in unidirectional communication with the stylus of the extractor member in the second direction, e.g. upward, for instance via the punch actuator. In a case of a respective unidirectional communication, movement of the stylus of the punch member in the second direction may be imparted to the stylus of the extractor member, whereas movement of the stylus of the punch member in the first direction, e.g. downward, may not be imparted to the stylus of the extractor member. In such embodiments moving the stylus of the extractor member in the direction opposite to the orientation of the opening of the tubular end portion of the punch member, e.g. upward, after inserting a selected portion of the tubular end portion of the extractor member into the tissue, may be achieved by moving the stylus of the punch member in the second direction, e.g. upward. Thereby the selected portion of the tubular end portion of the extractor member may be moved out of the tissue.

[0092] In embodiments where the stylus of the extractor member and the stylus of the punch member are arranged in an at least substantially parallel way they may have the same orientation, i.e. both openings of the two styli may point in the same direction. In these embodiments the first direction, defined by the orientation of the opening of the tubular end portion of the stylus of the punch member, may also be defined by the orientation of the opening of the tubular end portion of the stylus of the extractor member. In such an embodiment moving the stylus of the punch member in the second direction, e.g. upward, may include moving both styli, the stylus of the extractor member and the stylus of the punch member, in the second direction, e.g. upward. In some embodiments the punch actuator is allowed to actuate the stylus of the punch member, thereby actuating the extractor member. Where both members are arranged at least substantially parallel and in the same orientation, the punch actuator moves both styli in the same direction. As explained above, the unidirectional communication of the two styli may in some embodiments be a unidirectional coupling that causes the stylus of the extractor member to move by at least substantially the same distance by which the stylus of the punch member moves.

[0093] As also explained above, the stylus of the punch member, in communication with the stylus of the extractor member, may in some embodiments be arrested in its position as soon as a stylus of the extractor member, which may include the tubular end portion thereof, is no longer inserted in the tissue. In this way information on the distance, by which the extractor member moved out of the tissue is being stored by the apparatus. In addition to this purely mechanic storage, information on the distance may also be stored on a memory device and, where required, be processed to calculate a distance of movement or a force of actuation that would be required to move the stylus of the punch member by the same distance. Thus the stylus of the punch member may be moved by the same distance in the opposite direction to the direction in which the stylus of the extractor member has moved out of the tissue - the first of which may be the second direction and the second may be the first direction as defined above. In embodiments where the stylus of the punch member and the stylus of the extractor member are coupled to move unidirectionally or in converse directions by the same distance, no further processing or conversion of data may be required.

[0094] In one embodiment the stop position of the stylus of the punch member and the stop position of the stylus of the extractor member correspond to each other. In this embodiment the tubular end portion of the extractor member has been inserted into the tissue while the stylus of the extractor member was arranged in its stop position (supra), for example. In this embodiment the stylus of the punch member was also arranged in its stop position while the stylus of the extractor member was for instance arranged in its stop position. If in this embodiment the stylus of the punch member is arrested once the stylus of the extractor member is no longer inserted into the tissue, both styli have been moved by about the same distance from their stop position. The distance by which the stylus of the punch member can be moved in the direction of the tissue, i.e. the first direction, until it reaches the stop position is at least substantially identical to the distance by which the stylus of the extractor member has been moved out of the tissue. This distance is also at least substantially identical to the width (i.e. height) of the tissue sample accommodated in the tubular end portion of the extractor member stylus along the length of the stylus. Driving the tubular end portion of the punch member, typically of the stylus of the punch member, by this distance into the recipient will therefore create a cavity of a depth in the dimension of the direction of the movement of the stylus of the punch member that corresponds to the dimension of the tissue sample in the direction of the axis defined by the extractor member stylus. [0095] As already explained above, the dimensions of the end portions of the punch member and the extractor member can also be brought in line with each other in order to form a cavity that matches the dimension of the tissue sample in the dimension/direction perpendicular to the axis defined by the extractor member stylus. The person skilled in the art will therefore appreciate that using an apparatus of the invention it is possible to conveniently form an individual cavity that perfectly matches a collected tissue sample, typically immediately after or concurrently (e.g. synchronously) with collecting the tissue sample.

[0096] Li embodiments where the stylus of the punch member is arrested in its position, for example by arresting the punch actuator, as soon as the stylus of the extractor member is no longer inserted into the tissue, the unidirectional communication between the two styli may be released, e.g. abandoned, once the punch actuator is arrested. In some embodiments the unidirectional communication of the stylus of the punch member with the stylus of the extractor member is reversibly releasable. As an illustrative example, the unidirectional communication of the punch actuator with the stylus of the extractor member may be re-established once the tissue sample is released from the tubular end portion of the extractor member (see also below). A new round of sample collection and recipient punching may then be initiated.

[0097] In the method of the invention the apparatus is further, generally after collecting the tissue sample, arranged to be in a location next to, on a top of, above or otherwise about an at least substantially solid recipient into which the tissue sample is to be deposited. In particular where the apparatus of the invention is portable, this transfer from the donor tissue to the recipient is convenient and time saving. Using the method of the invention a tissue array can thus be formed in situ, rather than moving recipient blocks around, which are a in some embodiments a clinical commodity and hence are subjected to stringent requirements of confidentiality and anonymity. Such a portable apparatus is also ideal to share between laboratories affiliated to the same research institute or core facility. It makes it particularly useful for those involved in tissue collections from different sources. Finally, the possibility of a very convenient design ("a pen" or "a pen in a case") makes the apparatus very easy to store, avoiding the need to occupy permanent space on laboratory benches.

[0098] The apparatus is brought into a position where the opening of the tubular end portion of the punch member is in contact with the recipient. The exact position of the contact point on the recipient may be predefined and for instance be marked, for example in the form of a grid. Fig. 23 depicts an example of a predefined pattern of positions for cavities to be formed on a recipient. Each position of the pattern may be a position onto which the tubular end portion of a punch member of an apparatus of the invention is to be arranged. As explained above, this end portion of the punch member may be part of the respective stylus. The apparatus may further be the same apparatus operated in a consecutive manner. A respective pattern, e.g. a grid, may also be drawn into adhesive tape. The operator may take some of this tape and stick it onto the recipient surface, providing a natural grid for the samples of a tissue array to be placed.

[0099] In embodiments where the tubular end portion of the punch member is connected to or included in the stylus of the punch member, the stylus of the punch member is moved in the direction defined by the orientation of the opening of the tubular end portion therof, e.g. downward. Moving the stylus of the punch member in the direction defined by the orientation of the opening of the tubular end portion may include operating at least one of the extractor actuator and the punch actuator. A selected portion of the end portion of the stylus of the punch member is inserted into the recipient. As a result a portion of the recipient is accommodated in the tubular end portion of the punch member. It may be advantageous to arrange the apparatus in such a way that the direction defined by the orientation of the tubular end portion of the punch stylus is close to, or even at least substantially about perpendicular to the corresponding surface area of the recipient. This increases predictability and reproducibility in the use of a tissue array formed by the method of the invention, for example in screening. It is further advantageous to select a recipient with an at least substantially straight, including flat, surface. This will facilitate the speed of operation as well as reproducibility. [0100] A cavity is formed as a result of moving the stylus of the punch member in the direction defined by the orientation of the opening of the tubular end portion thereof. In order to complete the formation of the cavity the stylus of the punch member is moved in the direction opposite to the orientation of the opening of the tubular end portion thereof. Depending on the rigidity and consistency of the recipient material, the punch member stylus may need to be rotated as indicated above. For embodiments where the recipient is a paraffin block, the present inventors have found that an angle of rotation of ± 30° is sufficient to break the burr and waste of paraffin and that a smooth hole is formed. The cavity formed has a maximal width, perpendicular to the direction in which the punch member stylus was inserted, that corresponds to the maximal outer width of the portion of the tubular end portion of the punch member inserted into the recipient.

[0101] The apparatus ^"is further brought into a position where the opening of the tubular end portion of the extractor member is positioned about the cavity formed in the recipient. The tubular end portion of the extractor member, and thus the opening thereof, is positioned in such a way that the tissue sample accommodated in the tubular end portion of the extractor member can be inserted into the cavity described above, e.g. that has just been formed. The tissue sample accommodated in the tubular end portion of the extractor member is released from the same. Thereby the tissue sample is inserted into the cavity that has been formed in the recipient. Releasing the tissue sample accommodated in the tubular end portion of the extractor member may include or be achieved by operating the extractor actuator. Operating the extractor actuator may for example include moving the stylus of the extractor member in the direction defined by the orientation of the tubular end portion thereof, such that the tissue sample accommodated in the tubular end portion of the extractor member is inserted into the cavity formed in the recipient. In some embodiments the apparatus may include an extractor ejector. Operating the extractor ejector may cause or assist the tissue sample accommodated in the tubular end portion of the extractor member stylus to be released, for instance as depicted in Fig. 2OL and Fig. 2OM. In some embodiments the ejector is coupled to the extractor actuator. This coupling may be designed in a way that operating the extractor actuator causes the tissue sample accommodated in the tubular end portion of the extractor member to be released.

[0102] In some of the embodiments where the stylus of the extractor member is movable within the tubular end portion of the extractor member such movement of the stylus is employed to release the tissue sample accommodated in the tubular end portion of the extractor member. As explained above, in some embodiments the stylus of the extractor member can hermetically seal the tubular end portion of the extractor member in the axial direction opposite to the opening of the tubular end portion. The opening of the tubular end portion may be hermetically sealed by the tissue sample accommodated therein (see above). Accordingly, releasing the tissue sample accommodated in the tubular end portion of the extractor member may include moving the stylus of the extractor member in the direction defined by the orientation of the opening of the tubular end portion thereof. The positive pressure generated my force the tissue sample to move in the direction of the opening of the tubular end portion and thereby leave the same.

[0103] The present invention also relates to a kit that includes an apparatus as defined above and a recipient (supra). The kit may further include tubular end portions of the extractor member and the punch member of various dimensions for replacing the end portions depending on the needs of e.g. an assay or a tissue. Tubular end portions in a variety of widths in both the axial dimension and the dimension perpendicular thereto may be provided. The kit may also include instructions, e.g. in the form of a leaflet or a manual, on how to carry out an embodiment of the method of the invention and/or on the use of an apparatus of the invention. [0104] The apparatus of the invention can be designed to be a manually operated apparatus that may conveniently be held in or by one hand. In particular in embodiments where the tubular end portion of the extractor member is an element of the apparatus that is separate from the stylus of the extractor member (see above) an apparatus of pen size can be provided that is capable of taking one or more tissue samples, forming matching cavities, e.g. holes, in a recipient and inserting the tissue samples therein. If desired, any part of the method of the invention may also be carried out in an automated manner. Accordingly, the apparatus of the invention may in some embodiments define or be included in a robot.

EXAMPLES [0105] The following non limiting examples are also illustrated by the accompanying drawings. Reference is therefore made to the respective figures.

[0106] Figure 1 depicts two exemplary embodiments of a portable apparatus according to the invention in a pen-like design. Figure IA shows an apparatus with a stylus (1) of a punch member and a stylus (2) of an extractor member. A tubular end portion of the punch member has an opening (41) that is in fluid communication with the ambience. A tubular end portion of the extractor member has an opening (42) that is in fluid communication with the ambience. Stylus (1) and stylus (2) are in communication via an automated depth device (10), which may be a mechanical or electronic device. A punch actuator (3) is in communication with the punch member and an extractor actuator (4) is in communication with the extractor member. A plate (31) can assist in holding the apparatus. Typical dimensions of the inner width of the stylus (2) which may correspond to the outer width of the stylus (1), matching sizes of tissue samples presently used in the art are shown below the apparatus. Figure IB shows an apparatus with a stylus (1) of a punch member and a stylus (2) of an extractor member. Stylus (1) and stylus (2) are in communication via an automated depth device (10), and stylus (1) is in communication with a punch actuator (3), and stylus (2) with an extractor actuator (4). The opening (41) of a tubular end portion of the punch member and the opening (42) of a tubular end portion of the extractor member are included in ports (66) and (65) of the housing (50) of the apparatus. Port (65) encompassing opening (42) can furthermore be covered by a lid (51). The apparatus further includes a handhold (14). [0107] Figure 2 depicts a further embodiment of an apparatus according to the invention. The apparatus includes a punch member (6) with a stylus and a tubular end portion (11) with an opening (41). The apparatus also includes an extractor member (7) with a stylus that has a tubular end portion (21) with an opening (42). A punch actuator (3) is coupled to the punch member (6) and an extractor actuator (4) is coupled to the extractor member (7). The punch member (6) is further unidirectionally coupled to the extractor member (7) via a punch bar (8) and an extractor bar (9). Via the same arrangement the extractor member (7) is also unidirectionally coupled to the punch member (6). The apparatus also includes a grip (14) that forms one physical unit together with a plate structure (13).

[0108] Figure 3 depicts a further embodiment of an apparatus according to the invention. A plate structure (13) serves as the platform to which all other parts can be assembled. This platform has a handle (14) that provides a holding place for the supporting hand of the operator. In the depicted example, the handle is located at the left (front view) for the right-handed operators. This can also be located at the right for the left-handed operators. The punch member includes a stylus in the form of a puncher (1), and the extractor member is designed in a form resembling a syringe. The punch member has a stylus (1) with a tubular end portion (11) that has an opening (41). The stylus (1) is accommodated by a punch holder (5). The extractor member has a stylus (2) with a tubular end portion (21) that has an opening (42). The operating procedure of the device is as follows. All of the assembly parts are first positioned at the home position (indicated by the dark grey structure). The punch actuator (3) is pulled up, i.e. in the axial direction of the extractor member stylus (2) opposite to the opening (42) of the tubular end portion (21) of the extractor member, to collect the tissue from the tissue dish (to be located below opening (42). Thereby the punch bar (8), coupled unidirectionally to the stylus (2) of the extractor member, is moved in the direction opposite to the orientation of opening (42). Thereby the extractor member stylus (2) is moved in this direction, i.e. upward. At the same time extractor bar (9) and extractor actuator (4) are moved in the same direction. Thus extractor member stylus (2), punch member stylus (1) and punch holder (5) are moved upward by the same distance. When tissue collection is finished, the next step is to align the tubular end portion (11) of the punch member with the surface of the recipient (to be located below opening 41). The next step is to move actuator (3) back to the home position to punch a hole into the recipient, e.g. a paraffin block. The depth of the hole will then be the same as the suction distance of the tissue, guaranteeing the same deposition volume by virtue of same cross section area of the end portions (21) and (11). To complete the hole, the stylus (1) of punch member can be rotated back and forth. Backward rotation can also be provided by springs, eliminating the necessity of actuating the stylus (1) of the punch member twice, e.g. manually.

[0109] Figure 4 depicts the parts of the assembled apparatus. By changing the position of the grip (14) the position and orientation of plate structure (13) and thereby of the entire apparatus can be modified. A housing (19) accommodates the stylus of the punch member (6) and provides a guiding means (indicated by grey dots) for the stylus of the extractor member (7). The stylus of the extractor member includes in the present embodiment inter alia a rod (25) and a suction pin (98). The tubular end portion (21) of the extractor member is however not included in the stylus of the extractor member. The stylus of the punch member includes in the present embodiment inter alia a rod (23) as well as the tubular end portion (11) of the punch member. The rod (25) of the extractor member (7) is coupled to an extractor actuator (4). The rod (23) of the punch member (6) is coupled to a punch actuator (3). The extractor actuator (4) is connected to a bar (9). The punch actuator (3) is also connected to a bar (8). The two bars (8,9) are arranged in an offset manner (cf. also Fig. 14). As a result the extractor actuator (4) is unidirectionally coupled to the punch member (6) and the punch actuator (3) is unidirectionally coupled to the extractor member (7). Thus operating the extractor actuator (4) by pressing it down, i.e. moving it in the direction of the opening (42) of the tubular end portion (21) of the extractor member (7), movement of rod (25) and of rod (23) in the same direction can be effected. Operating the extractor actuator (4) by lifting it upward, i.e. moving it opposite to the direction of the opening (42) of the tubular end portion (21) of the extractor member, only movement of rod (25) in the same direction, but not a movement of rod (23) is effected. Operating the punch actuator (3) by lifting it upward, i.e. moving it opposite to the direction of the opening (41) of the tubular end portion (11) of the punch member, movement of rod (23) and of rod (25) in the same direction can be effected. Operating the punch actuator (3) by pressing it down, i.e. moving it in the direction of the opening (41) of the tubular end portion (11) of the punch member (6), however only effects movement of rod (23), but not of rod (25) in the same direction. The extractor member (7) includes a rubber (24), a rod (25), a rod end portion (26) serving as a connector, a suction piston (98) with a suction piston end portion (27), and a tubular end portion (21) of the extractor member with an opening (42). The punch member (6) includes a rubber (22), a rod (23), a recipient remover (18), a coil spring (17), two wire springs (16) and a tubular end portion (11) with an opening (41).

[0110] Figure 5 shows the plate structure (13) before being assembled into the apparatus of the invention. It is of a shape such that it is convenient to be held by one hand at the hand grip side (14). Assembly holes (33) are to mount the housing. An adjustment hole is provided to put stopper when necessary, or as a guide for vertical motion of the punch member and the extractor member.

[0111] Figure 6 depicts the housing (19) that has two guiding means in the form of hollow cylinders (40, 50) to provide guidance to the stylus of the punch member and the stylus of the extractor member. Cylinder (50) serves in guiding the punch to create a hole in the recipient. Cylinder (40) serves in guiding the stylus of the extractor member to collect and deliver tissue.

[0112] Figure 7 is a partial magnification of the punch member. A rod (23) is surrounded by a rubber (22) to slide through the guiding cylinder of the housing (19). The rod (23) is mounted to a punch container (47). The punch container partially encompasses the tubular end portion (11) of the punch member (11), which includes an opening (42), as well as a recipient remover (18). The tubular end portion (11) and the recipient remover (18) are separated by a coil spring (17). The tubular end portion (11) is guided by two wire springs (16). [0113] Figure 8 depicts an embodiment of the tubular end portion of the punch member, which is a removable hollow cylinder to punch a hole onto the recipient. A handle (35) is provided to rotate the recipient portion that is punched, thereby creating a complete, perfect hole. Wire springs will then return it to the original position.

[0114] Figure 9 depicts a paraffin remover, which may optionally be included in the apparatus. It is a cylinder with the same outer width (e.g. diameter) as the inner width of the tubular end portion of the punch member. A handle (36) is provided to push the remover down to remove the paraffin from the punch.

[0115] Figure 10 is an enlarged view of the extractor member. It includes a rod (25) with an end portion (26), a rubber (24), a suction piston (98) with an end portion (27), and a tubular end portion in the form of a needle (21) with an opening (42). The rod (25) is to slide through the guiding cylinder of the housing (cf. Fig. 6). The end portion (26) of the rod (25) serves as a connector (26) to connect the rod (25) and the suction piston (98) via the end portion (27) of the suction piston (98) so as to allow an exchange of the suction piston (98) and the tubular end portion (21) to adapt the apparatus to different sets of tissue sample width when required.

[0116] Figure 11 depicts an embodiment of the tubular end portion of the extractor member, which is a removable hollow cylinder to collect a tissue sample and to accommodate the same. The tubular end portion of the extractor member may include a thread for mounting purposes (not shown). [0117] Figure 12 depicts a suction piston, which is a solid cylinder with a rubber (99) attached to the end part for suction purposes. The width of the pin is the same as the inner width of the tubular end portion of the extractor member. The suction piston may include a thread for mounting purposes (not shown). [0118] Figure 13 is a schematic of a snap mechanism that may be used to secure the punch actuator and/or the extractor actuator by means of geometric fit. The same mechanism may also be used for other elements or portions of the apparatus where for instance a stylus is to be arrested. [0119] Figure 14 is an enlarged view depicting the punch actuator (3) and the extractor actuator (4). A punch bar (8) is connected to the punch actuator (3) and an extractor bar (9) is connected to the extractor actuator (4). Geometric overlap of the two offset bars provides unidirectional coupling between them, coupling one actuator to the other only in one direction.

[0120] Figure 15 depicts an alternative means of providing communication between the punch member and the extractor member in the form of a lever (cf. also Fig. 17 and Fig. 18). A lever with a fixed amplification ratio is selected; which is 1-1 in the current version. Fig. 15 A shows the central parts of the lever mechanism that allow the stylus of the extractor member and the stylus of the punch member to be in reciprocal communication. A bar (108) has a ball shaped recess (55). The dimensions of the recess (55) match the dimensions of the ball-shaped fulcrum (54), such that inserting the fulcrum (45) into the recess (55) provides a lever. Pivoting the bar (108) in the transverse axis of rotation of the fulcrum (54) causes the ends of the bar (108) to move up and down. Such movement is imparted to any stylus that may be in communication with, including coupled to, the bar (108). One stylus is typically coupled to one side of the bar (108) - relative to the recess (55) - while another stylus is coupled to the other side. If the positions of the bar (108), to which the styli are coupled, are located equidistance from the recess (55) the two styli are coupled to move in opposite directions by the same distance. Pivoting the bar (108) in the axis of rotation of the fulcrum (54) causes a clockwise or counter-clockwise rotation of the ends of the bar (108) around the fulcrum (54). Such movement can be employed to bring one of the styli into a position where it can be decoupled from the bar (108). Fig. 15B shows the coupling of the extractor actuator (3) and the punch actuator (4) to the lever. The punch actuator (4) and the extractor actuator (3) are located equidistance from the recess (55). The vertical motion of one stylus is, therefore, the same as the other stylus. The ball-shaped recess (55) of the lever rests on a ball-shaped fulcrum (54) and is thus in communication with other elements of the apparatus such as a housing. The stylus of the punch member and the stylus of the extractor member are not shown for the sake of clarity. The stylus of the punch member could for example be arranged at a position on the bar (108), left of the fulcrum (54), whereas the stylus of the extractor member could arranged at a position right of the fulcrum (54), at the same distance from the fulcrum (54) as the punch member. [0121] Figure 16 depicts an embodiment of the use of an apparatus of the invention. The apparatus has a unidirectional coupling between the stylus of the extractor member and the stylus of the punch member as well as a unidirectional coupling between the stylus of the punch member and the stylus of the extractor member that generally corresponds to the embodiment depicted in Fig. 4 and in Fig. 14. Li this embodiment the tubular end portion (102) of the extractor member is capable of accommodating a stylus (15) of the extractor member. The outer width of the stylus (15) matches the inner width of the tubular end portion (102), thereby hermetically sealing the side of the tubular end portion (102) that is arranged axially opposite to the opening (42) thereof. The stylus (15) is movable in the tubular end portion (102) in the axial direction. The stylus (1) includes the tubular end portion of the punch member. For sake of clarity only a portion of the stylus (1) is shown that has a tubular end portion. A: The apparatus is positioned about a tissue or tissue portion (100) such that the tubular end portion of the extractor member (102) can be inserted into the tissue. The tubular end portion of the stylus of the punch member (1) is not required at this stage. Relative to the housing that is included in the apparatus (not shown) both the punch member and the extractor member are in a predefined start position. B: The apparatus is moved in the direction defined by the orientation of the tubular end portion of the extractor member. The tubular end portion of the extractor member (102) is thereby inserted into the tissue (100). C: The stylus (1) of the punch member is moved in the direction opposite to the orientation of the opening (41) of the tubular end portion thereof. Due to the unidirectional coupling of the stylus (1) of the punch member to the stylus (15) of the extractor member the stylus (15) of the extractor member (1) is moved in the same direction by the same distance, thereby drawing tissue into the tubular end portion (102). A tissue sample (110) is thereby transferred from the tissue (100) into the tubular end portion (102). D: The apparatus is moved in the direction opposite to the orientation of the opening (42) of the tubular end portion (102). Thereby the tubular end portion (102) is removed out of the tissue (100). The tissue sample (110), still accommodated by the tubular end portion (102), is thereby removed from the tissue (100). E: The apparatus of the invention is brought into proximity to an at least substantially solid recipient (101). F: The stylus (15) of the extractor member is moved in the direction opposite to the orientation of the tubular end portion thereof. Due to the unidirectional coupling of the stylus (1) of the punch member to the stylus (15) of the extractor member in this direction, no movement is imparted to the stylus (1) of the punch member. G: The apparatus is brought into a position where the opening of the tubular end portion of the stylus (1) of the punch member is in contact with the recipient (101). H: The punch member is moved in the direction defined by the orientation of the opening of the tubular end portion thereof. The tubular end portion of the punch member is thereby inserted into the recipient, such that a portion of the recipient is accommodated in the tubular end portion of the punch member. As the stylus (1) of the punch member is thereby returned to the predefined start position within the apparatus, the tubular end portion is moved into the recipient by the same distance that the stylus (15) of the extractor member has previously been moved in the axial direction opposite to opening (42) (see step C). I: The stylus (1) of the punch member is rotated axially clockwise and anticlockwise. Thereby a portion (111) of the recipient is loosened and disconnected from the residual recipient. J: The apparatus is moved in the direction opposite to the orientation of the tubular end portion of the punch member, thereby lifting the stylus (1) of the punch member out of the recipient. Thus a cavity (12) is formed in the recipient, which has a maximal width that corresponds to the maximal outer width of the tubular end portion of the punch member included in the stylus (1) thereof, which was inserted into the recipient (101). K: The apparatus is brought into a position where the opening of the tubular end portion of the extractor member is positioned about the cavity formed in the recipient, such that the tissue sample (110) accommodated in the tubular end portion of the extractor member can be inserted into the cavity. L: The tissue sample (110) accommodated in the tubular end portion of the extractor member is released from the same and thereby inserted into the cavity formed in the recipient.

[0122] Figure 17 depicts an embodiment of the use of an apparatus of the invention, in which an apparatus is used that has a different unidirectional coupling between the stylus of the punch member and the stylus of the extractor member when compared to the apparatus used in Fig. 16. The apparatus includes a first guiding means (94) providing fixation to the stylus (15) of the extractor member inside a housing (19). The apparatus further includes a second guiding means (95) providing fixation to the stylus (1) of the punch member inside the housing (19). In this embodiment the stylus of the punch member of the apparatus is in communication with the stylus of the extractor member in a reciprocal relationship. As a result movement of the stylus of the punch member in the direction defined by the opening of the tubular end portion thereof effects movement of the stylus of the extractor member in the direction opposite to the opening of the tubular end portion of the extractor member and vice versa. The coupling of the two styli resembles a teeterboard. Accordingly the two styli can be taken to be the two legs of the teeterboard, coupled to the bar (108). A fulcrum (54) provides the pivotal point of the teeterboard. Similar to the embodiment used in the method shown in Fig. 16, the tubular end portion (102) of the extractor member is capable of accommodating a stylus (15) of the extractor member. The outer width of the stylus (15) matches the inner width of the tubular end portion (102), such that there is a tight fit between the tubular end portion (102) and the stylus (15). The stylus (15) is movable in the tubular end portion (102) in the axial direction. The stylus (1) of the punch member includes the tubular end portion of the same. The tubular end portion of the stylus of the punch member (1) ends in a spacer (96), in which the stylus (15) is movable in the axial direction (axially movable). A: The apparatus is positioned about a tissue or tissue portion (100) such that the tubular end portion of the extractor member (102) can be inserted into the tissue. Relative to the housing that is included in the apparatus (not shown) the stylus (15) is arranged in a predefined position. This position is typically a stop position from where the stylus (15) can only be moved opposite to the direction of the opening (42) of the extractor member, but not in the direction of the opening. Due to the reciprocal coupling of the two styli, the stylus (1) of the punch member is arranged in a predefined position. Typically this position is a stop position from where the stylus (1) can only be moved in the direction of the opening (41) of the punch member, but not in the direction opposite to the direction of the opening. B: The apparatus is moved in the direction defined by the orientation of the tubular end portion (102) of the extractor member. The tubular end portion of the extractor member (102) is thereby brought into contact with the tissue (100). C: The apparatus is moved further in the direction defined by the orientation of the tubular end portion (102) of the extractor member. The tubular end portion of the extractor member (102) is thereby inserted into the tissue (100). D: The stylus (1) of the punch member with the tubular end portion is moved in the direction of the orientation of the opening (41) of the tubular end portion thereof. Due to the reciprocal coupling of the stylus (1) of the punch member to the stylus (15) of the extractor member the stylus (15) of the extractor member is moved in the direction opposite to the tubular end portion of the opening of the extractor member. As the distance between the stylus (1) and the fulcrum of the lever and the distance between the stylus (15) and the fulcrum of the lever are the same, the distance by which stylus (1) is moved is the same as the distance by which stylus (15) is moved. The movement of stylus (15) away from the tissue (100) creates a negative pressure in the tubular end portion (102) of the extractor member. Thereby tissue is drawn into the tubular end portion (102). A tissue sample (110) is thereby transferred from the tissue (100) into the tubular end portion (102). The movement of stylus (1) of the punch member in the direction of the orientation of the opening (41) of the tubular end portion thereof has furthermore caused the stylus (1) to be moved out of the spacer (96). The distance by which the stylus (1) protrudes out of the spacer (96), i.e. the distance by which the stylus (1) has moved, is the same distance as the distance by which stylus (15) has moved in the direction opposite to the tubular end portion of the opening of the extractor member. E: The apparatus is moved in the direction opposite to the orientation of the opening (42) of the tubular end portion (102) of the extractor member. Thereby the tubular end portion (102) is drawn out of the tissue (100). A tissue sample (110), accommodated by the tubular end portion (102) of the extractor member, is thereby removed from the tissue (100). F: The apparatus is arranged to be positioned in proximity to an at least substantially solid recipient (101). G: The apparatus is further moved in the direction defined by the opening (41) of the tubular end portion of the punch member. Thereby the stylus (1) of the punch member is inserted into the recipient (101). As the movement of the apparatus is limited by the spacer (96), the distance by which the stylus (1) protrudes out of the spacer (96) is the distance by which the stylus (1) can be inserted into the recipient (101). This distance is the distance by which the stylus (15) of the extractor member has moved in the direction opposite to the tubular end portion of the opening of the extractor member and thereby drawn a tissue sample from tissue (100). H: The apparatus is moved in the direction opposite to the orientation of the tubular end portion of the punch member, thereby lifting the stylus (1) of the punch member out of the recipient. Thus a cavity (12) is formed in the recipient, which has a maximal width that corresponds to the maximal outer width of the tubular end portion of the punch member included in the stylus (1) thereof, which was inserted into the recipient (101). I: The apparatus is brought into a position where the opening of the tubular end portion of the extractor member is positioned about the cavity formed in the recipient. Accordingly the tissue sample (110) accommodated in the tubular end portion (102) of the extractor member can be inserted into the cavity (12). J: The stylus (15) of the extractor member is moved in the direction of the orientation of the opening of the tubular end portion of the extractor member. Thereby the tissue sample (110) accommodated in the tubular end portion of the extractor member is released from the same and thereby inserted into the cavity formed in the recipient. K: The apparatus is brought into a position where the opening of the tubular end portion of the punch member as well as the spacer (96) are positioned about a recipient portion reservoir (69). Accordingly, the portion (111) of the recipient that is accommodated in the tubular end portion of the punch member can be inserted into the reservoir (69). L: A punch ejector (71) is inserted into the tubular end portion of the punch member by moving it in the direction of the opening of the tubular end portion of the punch member. It is brought into a position where it can assist in or achieve ejection of the portion (111) of the recipient. M: The punch ejector (71) is moved further in the direction of the opening of the tubular end portion of the punch member. Thereby the portion (111) of the recipient accommodated in the tubular end portion of the punch member is released from the same and inserted into the recipient portion reservoir (69). [0123] Figure 18 also depicts an embodiment of a method in which an apparatus is used in which the stylus of the punch member of the apparatus is in communication with the stylus of the extractor member in a reciprocal relationship (cf. Fig. 17). The two styli or coupled via a bar (108) pivotally mounted onto a fulcrum (54). The stylus (15) of the extractor member is further movable within the tubular end portion (102) of the extractor member. The two styli are arranged in a housing (19), where a first guiding means (94) guides the stylus (15) of the extractor member and a second guiding means (95) guides the stylus (1) of the punch member. A: The apparatus is arranged about a tissue or tissue portion (100) in a position that allows the tubular end portion of the extractor member (102) to be inserted into the tissue. The stylus (15) is arranged in a predefined position, typically a stop position from where the stylus (15) can only be moved opposite to the direction of the opening (42) of the extractor member, but not in the direction of the opening. The same applies mutatis mutandis to the stylus (1) of the punch member. Typically stylus (1) can only be moved in the direction of the opening (41) of the punch member, since the two styli are reciprocally coupled. B: The apparatus is moved in the direction defined by the orientation of the tubular end portion (102) of the extractor member, such that the tubular end portion of the extractor member (102) is brought into contact with the tissue (100). C: Further movement of the apparatus in the direction defined by the orientation of the tubular end portion (102) of the extractor member causes insertion of the tubular end portion of the extractor member (102) into the tissue (100). D: The stylus (1) of the punch member with the tubular end portion is moved in the direction of the orientation of the opening (41) of the tubular end portion thereof. Thereby the stylus (1) is caused to protrude out of the spacer (96). Due to the reciprocal coupling of the styli the stylus (15) of the extractor member is moved in the direction opposite to the tubular end portion of the opening of the extractor member. It is moved by the same distance by which stylus (1) has protruded out of the spacer (96). The movement of stylus (15) away from the tissue (100) creates a negative pressure in the tubular end portion (102) of the extractor member. Thereby tissue is drawn into the tubular end portion (102). A tissue sample (110) is thereby transferred from the tissue (100) into the tubular end portion (102). E: The apparatus is moved in the direction opposite to the orientation of the opening of the tubular end portion (102) of the extractor member inserted into the tissue (100). Thereby the tubular end portion (102) is drawn out of the tissue (100). A tissue sample (110), accommodated by the tubular end portion (102) of the extractor member, is thereby removed from the tissue (100). F: The bar (108) coupling the two styli is slightly rotated around the fulcrum (54), such that the coupling of the stylus (15) of the extractor member to the bar (108) is released, i.e. countermanded. G: The entire extractor member, including the stylus (15) thereof and the tubular end portion (102) of the extractor member, is moved further in the direction opposite to the opening of the tubular end portion (102) of the extractor member, accommodating the tissue sample (110). Since the coupling between the two styli is released, the movement of the stylus (15) associated with this move of the entire extractor member is not imparted to the stylus (1) of the punch member. The apparatus is further arranged to be positioned about, including close to and in proximity to, an at least substantially solid recipient (101). H: The apparatus is moved in the direction defined by the opening (41) of the tubular end portion of the punch member (included in the stylus thereof). Thereby the stylus (1) of the punch member is inserted into the recipient (101). The movement of the apparatus is limited by the spacer (96). Therefore the distance by which the stylus (1) is inserted into the recipient (101) is the distance by which the stylus (1) protrudes out of the spacer (96). This distance is also the distance by which the stylus (15) of the extractor member has moved in the direction opposite to the tubular end portion of the opening of the extractor member and thereby drawn a tissue sample from tissue (100). I: The stylus (1) of the punch member is moved in the direction opposite to the orientation of the tubular end portion of the punch member, thereby lifting the stylus (1) of the punch member out of the recipient. This can be done without moving the entire apparatus. In this case the bar (108) is pivoted, such that the end of the bar (108) that is in proximity to the stylus (15) of the extractor member is lowered, i.e. moved in the direction of the recipient (101), corresponding to the direction of the opening of the tubular end portion of the extractor member. Since the coupling of the stylus (15) of the extractor member to the bar (108) is released, no movement of stylus (15) in the direction of the opening of the end portion of the extractor member occurs. By moving the stylus (1) of the punch member out of the recipient (101) a cavity (12) is formed in the recipient. This cavity (12) has a maximal width that corresponds to the maximal outer width of the tubular end portion of the punch member included in the stylus (1) thereof, which was inserted into the recipient (101). J: The apparatus is brought into a position where the opening of the tubular end portion of the extractor member, which includes the tissue sample (110), is positioned about the cavity formed in the recipient. The tissue sample (110) accommodated in the tubular end portion (102) of the extractor member can thus be inserted into the cavity (12). Optionally the entire extractor member, including the tubular end portion (102) and the stylus (15) thereof, can be moved in the direction of the opening of the tubular end portion (102). The coupling of the stylus (15) of the extractor member to the bar (108) and thus also to the stylus (1) of the punch member is still released, such a movement can occur independently of the position of the stylus (1) of the punch member. K: The stylus (15) of the extractor member is moved in the direction of the orientation of the opening of the tubular end portion of the extractor member. Thereby the tissue sample (110), accommodated in the tubular end portion of the extractor member, is released from the tubular end portion and thereby inserted into the cavity formed in the recipient.

[0124] Figure 19 depicts a further embodiment of the use of an apparatus of the invention. In this embodiment the tubular end portion of the extractor member is a part of the stylus (2) of the extractor member. Accordingly, a movement of the stylus of the extractor member includes a movement of the tubular end portion thereof. A: The apparatus is positioned about a tissue or tissue portion (100) such that the end portion of the stylus of the extractor member (2) can be inserted into the tissue. The tubular end portion of the stylus of the punch member (1) is not required at this stage. Relative to the housing that is included in the apparatus (not shown) both the punch member and the extractor member are in a predefined start position. B: The apparatus is brought into a position where the opening (42) of the tubular end portion of the stylus of the extractor member (2) is in contact with the tissue and moved further in the direction defined by the orientation of the tubular end portion of the stylus of the extractor member. A selected portion of the tubular end portion of the stylus of the extractor member (2) is thereby inserted into the tissue (100). C: The stylus (2) of the extractor member is moved in the direction opposite to the orientation of the opening of the tubular end portion thereof until the tubular end portion leaves the tissue (100). A tissue sample (110) is thereby removed from the tissue (100), being accommodated by the tubular end portion (2). Due to the unidirectional coupling of the stylus of the punch member to the stylus of the extractor member the tubular end portion of the stylus of the punch member (1) is moved in the same direction by the same distance. D: The apparatus of the invention is brought into proximity to an at least substantially solid recipient (101). E: The apparatus is brought into a position where the opening (41) of the tubular end portion of the punch member (1) is in contact with the recipient (101). F: The stylus of the punch member (1) is moved in the direction defined by the orientation of the opening of the tubular end portion thereof. A selected portion of the tubular end portion of the punch member is thereby inserted into the recipient, such that a portion of the recipient is accommodated in the tubular end portion of the punch member. As the stylus of the punch member (1) is thereby returned to the predefined start position, the tubular end portion is moved into the recipient by the same distance that the tubular end portion of the stylus of the extractor member (2) has previously been inserted into the tissue (see step B). G: The stylus of the punch member (1) is moved in the direction opposite to the orientation of the opening of the tubular end portion thereof. Thus a cavity (12) is formed in the recipient, which has a maximal width that corresponds to the maximal outer width of the portion of the tubular end portion of the punch member inserted into the recipient (101). H: The apparatus is brought into a further distance to the recipient (101), such that the portion (111) of the recipient that is accommodated in the tubular end portion of the punch member is removed from the recipient. I: The apparatus is brought into a position where the opening of the tubular end portion of the extractor member is positioned about the cavity formed in the recipient, such that the tissue sample (110) accommodated in the tubular end portion of the extractor member can be inserted into the cavity. J: The tissue sample (110) accommodated in the tubular end portion of the extractor member is released from the same and thereby inserted into the cavity formed in the recipient. [0125] Figure 20 depicts a further embodiment of the use of an apparatus of the invention where the tubular end portion of the extractor member is a part of the stylus (2) of the extractor member. A: The apparatus is positioned about a tissue or tissue portion (100) such that the end portion of the stylus of the extractor member (2) can be inserted into the tissue. Relative to the housing that is included in the apparatus (not shown) both the punch member stylus (1) and the extractor member stylus (2) are in a predefined start position. B: The apparatus is moved in the direction defined by the orientation (42) of the opening of the tubular end portion of the stylus of the extractor member. A selected portion of the tubular end portion of the stylus of the extractor member (2) is thereby inserted into the tissue (100). C: The extractor member stylus (2) is moved in the direction opposite to the orientation of the tubular end portion thereof until the tubular end portion (2) leaves the tissue (100). A tissue sample (110) is thereby removed from the tissue (100), being accommodated by the tubular end portion of the stylus (2) of the extractor member. Due to the unidirectional coupling of the stylus of the punch member to the stylus of the extractor member the tubular end portion of the stylus of the punch member (1) is moved in the same direction by the same distance. D: The unidirectional coupling of the stylus of the punch member to the stylus of the extractor member is released. Only the stylus (2) of the extractor member is moved further in the direction that is opposite to the opening (42) of the end portion thereof. The stylus (1) of the punch member is being arrested in its current position. E: The apparatus of the invention is brought into proximity to an at least substantially solid recipient (101). F: The apparatus is brought into a position where the opening of the tubular end portion of the punch member (1) is in contact with the recipient (101). G: The stylus (1) of the punch member is moved in the direction defined by the orientation of the opening of the tubular end portion thereof. A selected portion of the tubular end portion of the punch member is thereby inserted into the recipient, such that a portion of the recipient is accommodated in the tubular end portion of the punch member. H: The stylus (1) of the punch member is moved in the direction opposite to the orientation of the opening of the tubular end portion thereof. Thus a cavity (12) is formed in the recipient (101), which has a maximal width that corresponds to the maximal outer width of the portion of the tubular end portion of the punch member inserted into the recipient (101). I: The apparatus is brought into a further distance to the recipient (101), such that the portion (111) of the recipient that is accommodated in the tubular end portion of the punch member is removed from the recipient (101). J: The stylus (2) of the extractor member is moved into the direction defined by the opening of the tubular end portion thereof. Optionally the stylus of the punch member may be moved into the direction opposite to the opening of the tubular end portion (1) thereof. K: The apparatus is brought into a position where the opening of the tubular end portion of the extractor member is positioned about the cavity formed in the recipient (101), such that the tissue sample (110) accommodated in the tubular end portion of the extractor member can be inserted into the cavity. L: An extractor ejector (72) is brought into a position where it can assist in or achieve ejection of the tissue sample (110) from the tubular end portion (2) of the extractor member. M: The tissue sample (110) accommodated in the tubular end portion of the extractor member is released from the same by means of the extractor ejector (72) and thereby inserted into the cavity formed in the recipient. N: The apparatus is brought into a position where the opening of the tubular end portion of the punch member is positioned about a recipient portion reservoir (69), such that the portion (111) of the recipient that is accommodated in the tubular end portion of the punch member can be inserted into the reservoir (69). O: A punch ejector (71) is brought into a position where it can assist in or achieve ejection of the portion (111) of the recipient from the tubular end portion (1) of the punch member. P: The portion (111) of the recipient accommodated in the tubular end portion of the punch member is released from the same by means of the punch ejector (71) and thereby inserted into the recipient portion reservoir (69).

[0126] Figure 21 depicts a rotation mechanism for rotating the tubular end portion of the punch member, which is in typical embodiments included in the stylus of the punch member, in top view (A) and the respective stylus in cross-sectional view (B). Moving the handle in the counter-clockwise direction causes turning, thereby rotating the stylus (43) of the punch member 44: spiral spring; 45: handle, 43: stylus.

[0127] Figure 22 depicts a kit that includes the apparatus (50) of the invention contained in a suitcase (57). The apparatus (50) is arranged above a recipient (58), both of which being arranged on a stage (59). A slider (56) may be used to assist in positioning the apparatus (50). A control panel (54) and an LCD (63) may serve in operating the apparatus in an automated manner.

[0128] Figure 23 depicts an adhesive grid that may be positioned and optionally immobilised on the recipient.

[0129] Figure 24 depicts positioning the adhesive grid (75) on a recipient (101), which may be placed on a recipient holder (74) of a suitcase as e.g. shown in Fig. 22 or Fig. 25 (73: tissue holder).

[0130] Figure 25 depicts a further example of a kit, which includes an arrangement of an apparatus of the invention contained in a suitcase. 73: tissue holder; 74: recipient holder; 76: light;

77: cover; 78: light cover resting bay; 79: bay for adhesive tape with grid; 83: drawer for tissue holder; 84: drawer: refill for the apparatus of the invention; 85: base; 86: foldable holder for the apparatus of the invention; 87: bay for tissue paper; 88: bay for cleaning solution; 89: handle.

[0131] Figure 26 depicts the arrangement of the kit of Fig. 25 in top view. 73: tissue holder; 74: recipient holder; 78: light cover resting bay; 79: bay for adhesive tape with grid;

83: drawer for tissue holder; 84: drawer: refill for the apparatus of the invention; 87: bay for tissue paper; 88: bay for cleaning solution; 93: bay for the apparatus of the invention and for a foldable holder therefore.

[0132] Figure 27 briefly illustrates an embodiment of a method of the invention. A: The apparatus is in a position where the opening of the tubular end portion of the extractor member is in contact with a tissue (100) and the stylus (2) of the extractor member is moved in the direction defined by the orientation of the tubular end portion thereof by operating the extractor actuator (4). The tubular end portion the extractor member is thus inserted into the tissue, such that a tissue sample is accommodated in the tubular end portion of the extractor member. B: The tubular end portion of the stylus of the extractor member accommodates the tissue sample (110) taken from the tissue. The apparatus is positioned about an at least substantially solid recipient (101) in such a manner that the opening of the tubular end portion of the punch member is in contact with the recipient. The stylus (1) of the punch member is moved in the direction defined by the orientation of the tubular end portion thereof by operating the punch actuator (3), thereby inserting the tubular end portion of the punch member into the recipient. As a result a portion (111) of the recipient is accommodated in the tubular end portion of the punch member and a cavity is formed in the recipient. C: The apparatus is brought into a position where the opening of the tubular end portion of the extractor member is positioned about the cavity formed in the recipient. By operating the extractor actuator (4) the tissue sample (110) accommodated in the tubular end portion of the extractor member is released from the same and thus inserted into the cavity formed in the recipient. D: The portion (111) of the recipient accommodated in the tubular end portion of the punch member is released from the same by operating the punch actuator (3).

[0133] The listing or discussion of a previously published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0134] The invention illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms "comprising", "including," containing", etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by exemplary embodiments and optional features, modification and variation of the inventions embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.

[0135] The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0136] Other embodiments are within the following claims. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.

Claims

ClaimsWhat is claimed is:

1. An apparatus for forming a tissue array in an at least substantially solid recipient, comprising: - an extractor member comprising a stylus and a tubular end portion for accommodating a tissue sample, the tubular end portion having an opening,

- a punch member comprising a stylus and a tubular end portion for accommodating matter punched from the recipient, the tubular end portion having an opening,

- a housing comprising a first guiding means and a second guiding means, the first guiding means providing fixation to the stylus of the extractor member inside the housing, such that the stylus of the extractor member is movable in the axial direction, and the second guiding means providing fixation to the stylus of the punch member inside the housing, such that the stylus of the punch member is movable in the axial direction, wherein the punch member is in communication with a punch actuator and the extractor member is in communication with an extractor actuator.

2. The apparatus of claim 1, wherein the punch actuator is coupled to the stylus of the punch member in such a manner that operating the punch actuator effects a movement of the stylus of the punch member in the axial direction defined by the opening of the tubular end portion thereof.

3. The apparatus of claims 1 or 2, wherein the extractor actuator is coupled to the stylus of the extractor member in such a manner that operating the extractor actuator effects a movement of the stylus of the extractor member in the axial direction defined by the opening of the tubular end portion thereof.

4. The apparatus of any one of claims 1 - 3, wherein the tubular end portion of the punch member is comprised in the stylus of the punch member, thereby defining a tubular end portion of the stylus.

5. The apparatus of any one of claims 1 - 4, wherein the opening of the tubular end portion of the punch member is girded by an edge.

6. The apparatus of claim 5, wherein the tubular end portion of the punch member is capable of accommodating matter punched by the edge from the recipient.

7. The apparatus of any one of claims 1 - 6, wherein the opening of the tubular end portion of the extractor member is girded by an edge.

8. The apparatus of claim 7, wherein the edge of the tubular end portion of the extractor member has a shape selected from the group of ovoid shape, at least substantially circular shape and the shape of a polyhedron.

9. The apparatus of claims 7 or 8, wherein the edge of the tubular end portion of the stylus of the extractor member is arranged in a plane that is at least substantially perpendicular to the axis defined by the length of the stylus.

10. The apparatus of any one of claims 7 - 9, wherein the tubular end portion of the extractor member is capable of accommodating a tissue sample punched by the edge.

11. The apparatus of any one of claims 7 - 10, wherein the apparatus is an apparatus of forming a micro tissue array and wherein the edge of the tubular end portion of the stylus of the extractor member has a maximal width of about 5 mm or below.

12. The apparatus of claim 11, wherein the edge of the tubular end portion of the stylus of the extractor member has a maximal width of about 2 mm or below.

13. The apparatus of any one of claims 5 - 12, wherein both the tubular end portion of the extractor member and the tubular end portion of the punch member are girded by an edge and wherein the edge of the tubular end portion of the extractor member has a maximal inner width that is of at most about the same size as the minimal outer width of the edge of the tubular end portion of the punch member.

14. The apparatus of any one of claims 5 - 13, wherein both the tubular end portion of the extractor member and the tubular end portion of the punch member are girded by an edge and wherein the two edges are of at least substantially the same shape.

15. The apparatus of any one of claims 5 - 14, wherein both the tubular end portion of the extractor member and the tubular end portion of the punch member are girded by an edge, both edges being of circular shape, and wherein the inner width of the edge of the tubular end portion of the stylus of the extractor member and the outer width of the edge of the tubular end portion of the stylus of the punch member are the same.

16. The apparatus of any one of claims 1 - 15, wherein the stylus of the punch member is in communication with the stylus of the extractor member in a reciprocal relationship, such that movement of the stylus of the punch member in the direction of the opening of the tubular end portion thereof effects movement of the stylus of the extractor member in the direction opposite to the opening of the tubular end portion of the extractor member and vice versa.

17. The apparatus of any one of claims 1 - 15, wherein the stylus of the punch member is movable in a first and in a second axial direction, the first direction being defined by the orientation of the opening of the tubular end portion of the punch member and the second direction being opposite thereto, wherein the stylus of the punch member is in unidirectional communication with the stylus of the extractor member in the second direction, such that movement of the stylus of the punch member in the second direction is imparted to the stylus of the extractor member, whereas movement of the stylus of the punch member in the first direction is not imparted to the stylus of the extractor member.

18. The apparatus of claim 17, comprising a punch actuator, wherein the stylus of the punch member is in unidirectional communication with the stylus of the extractor member via the punch actuator.

19. The apparatus of claim 18, wherein the stylus of the punch member is in unidirectional communication with the stylus of the extractor member in such a manner that operating the punch actuator effects (i) a movement of the stylus of the punch member in the axial direction opposite to the opening of the tubular end portion thereof and (ii) a movement of the stylus of the extractor member in the axial direction opposite to the opening of the tubular end portion thereof.

20. The apparatus of any one of claims 1 - 19, wherein the stylus of the extractor member is in unidirectional communication with the stylus of the punch member in the direction defined by the orientation of the opening of the tubular end portion of the extractor member, such that movement of the stylus of the extractor member in the direction defined by the orientation of the opening of the tubular end portion of the extractor member is imparted to the stylus of the punch member, whereas movement of the stylus of the extractor member in the opposite direction is not imparted to the stylus of the punch member.

21. The apparatus of claim 20, comprising an extractor actuator, wherein the stylus of the extractor member is in unidirectional communication with the stylus of the punch member via the extractor actuator.

22. The apparatus of claim 21, wherein the stylus of the extractor member is in unidirectional communication with the stylus of the punch member in such a manner that operating the extractor actuator effects (i) a movement of the stylus of the extractor member in the axial direction of the opening of the tubular end portion thereof and (ii) a movement of the stylus of the punch member the axial direction defined by the opening of the tubular end portion thereof.

23. The apparatus of any one of claims 1 - 22, wherein the tubular end portion of the extractor member has an axis and wherein the axis of the tubular end portion and the axis of the stylus of the extractor member are at least substantially parallel to each other.

24. The apparatus of claim 23, wherein the stylus of the extractor member comprises a suction piston.

25. The apparatus of claim 24, wherein the suction piston is comprised in the tubular end portion of the stylus of the extractor member.

26. The apparatus of claim 25, wherein the suction piston is movable within the tubular end portion of the stylus of the extractor member.

27. The apparatus of any one of claims 24 - 26, wherein the stylus of the punch member is movable in a first and in a second axial direction, the first direction being defined by the orientation of the opening of the tubular end portion of the stylus and the second direction being opposite thereto, wherein the punch member is unidirectionally coupled to the suction piston of the extractor member in the second direction, such that movement of the stylus of the punch member in the second direction is imparted to the suction piston of the extractor member, whereas movement of the stylus of the punch member in the first direction is not imparted to the suction piston of the extractor member.

28. The apparatus of any one of claims 24 - 27, wherein the stylus of the punch member is unidirectionally coupled to the suction piston of the extractor member, such that movement of the punch member by a defined distance is imparted to the suction piston of the extractor member to cause movement by the same defined distance.

29. The apparatus of any one of claims 1 - 28, wherein the stylus of the extractor member and the stylus of the punch member are arranged at least substantially parallel to each other.

30. The apparatus of any one of claims 24 - 28, wherein the suction piston of the extractor member and the stylus of the punch member are arranged at least substantially parallel to each other.

31. The apparatus of claim 30, wherein the stylus of the punch member is unidirectionally coupled to the suction piston of the extractor member to cause movement of the suction piston of the extractor member in at least substantially the same direction as the stylus of the punch member.

32. The apparatus of claim 31 , wherein the suction piston of the extractor member is further unidirectionally coupled to the stylus of the punch member.

33. The apparatus of claim 32, wherein the stylus of the punch member is movable in a first and in a second axial direction, the first direction being defined by the orientation of the opening of the tubular end portion of the stylus and the second direction being opposite thereto, wherein the suction piston of the extractor member is unidirectionally coupled to the stylus of the punch member in the second direction, such that movement of the stylus of the suction piston in the first direction is imparted to the stylus of the punch member, whereas movement of the suction piston in the second direction is not imparted to the stylus of the punch member

34. The apparatus of claim 33, wherein the suction piston of the extractor member is coupled to an extractor actuator, wherein the suction piston of the extractor member is in unidirectional communication with the stylus of the punch member in such a manner that operating the extractor actuator effects (i) a movement of the stylus of the extractor member in the axial direction defined by the opening of the tubular end portion thereof and (ii) a movement of the stylus of the punch member in the axial direction defined by the opening of the tubular end portion thereof.

35. The apparatus of claim 34, wherein the stylus of the punch member is unidirectionally coupled to the suction piston of the extractor member and wherein the suction piston of the extractor member is unidirectionally coupled to the stylus of the punch member in such a manner that (i) operating the extractor actuator effects a movement of the stylus of the extractor member and of the stylus of the punch in the axial direction defined by the opening of the tubular end portions and (ii) operating the punch actuator effects a movement of the stylus of the punch member and of the stylus of the extractor member in the axial direction opposite to the opening of the tubular end portions.

36. The apparatus of any one of claims 1 - 35, further comprising a stop position for the stylus of the extractor member, wherein the stop position limits the movement of the stylus in the direction defined by the opening of the tubular end portion of the extractor member.

37. The apparatus of any one of claims 24 - 28 and 30 - 36, further comprising a stop position for the stylus of the extractor member, wherein the stop position limits the movement of the suction piston comprised in the stylus of the extractor member in the direction defined by the opening of the tubular end portion of the extractor member.

38. The apparatus of any one of claims 1 - 37, further comprising a stop position for the stylus of the punch member, wherein the stop position limits the movement of the stylus in the direction defined by the opening of the tubular end portion of the punch member.

39. The apparatus of any one of claims 1 - 38 wherein the apparatus is portable.

40. The apparatus of claim 39, wherein the apparatus is a hand-held apparatus.

41. The apparatus of any one of claims 1 - 40, further comprising a handhold for holding the same.

42. The apparatus of any one of claims 1 - 41, further comprising an actuable lock coupled to the punch member, wherein actuation of the lock blocks movement of the punch member in the direction opposite to the opening of its tubular end portion.

43. The apparatus of any one of claims 1 - 42, wherein the stylus of the punch member is rotatable.

44. The apparatus of claim 43, wherein the punch member comprises means to rotate the stylus thereof.

45. The apparatus of claim 44, wherein the means to rotate the stylus of the punch member comprise one of a spring and a handle.

46. The apparatus of any one of claims 1 - 45, wherein the tubular end portion of the extractor member is removable.

47. The apparatus of any one of claims 1 - 46, wherein the tubular end portion of the punch member is removable.

48. The apparatus of any one of claims 1 - 47, wherein the stylus of the punch member is coupled to the punch actuator via a bar.

49. The apparatus of any one of claims 1 - 48, wherein the stylus of the extractor member is coupled to the extractor actuator via a bar.

50. The apparatus of any one of claims 1 - 49, wherein the extractor actuator is manually operatable.

51. The apparatus of any one of claims 1 - 50, wherein the extractor actuator is one of a mechanic, a magnetic, an electromagnetic, a hydraulic and a pneumatic actuator.

52. The apparatus of any one of claims 1 - 51, wherein the punch actuator is manually operatable.

53. The apparatus of any one of claims 1 - 52, wherein the punch actuator is one of a mechanic, a magnetic, an electromagnetic, a hydraulic and a pneumatic actuator.

54. The apparatus of any one of claims 1 - 53, wherein the punch actuator operates via a change of its position.

55. The apparatus of claim 54, wherein the position of the punch actuator is securable by a catch.

56. The apparatus of claim 55, wherein the catch is designed to secure the position of the punch actuator by means of geometric fit.

57. The apparatus of any one of claims 1 - 56, wherein the extractor actuator operates via a change of its position.

58. The apparatus of claims 57, wherein the position of the extractor actuator is securable by a catch.

59. The apparatus of claim 58, wherein the catch is designed to secure the position of the extractor actuator by means of geometric fit.

60. The apparatus of any one of claims 1 - 59, wherein the edge of the tubular end portion of the stylus of the extractor member has a maximal inner width that is of about the same size as the minimal outer width of the edge of the tubular end portion of the stylus of the punch member.

61. The apparatus of claim 60, wherein both the edge of the tubular end portion of the stylus of the extractor member and the edge of the tubular end portion of the stylus of the punch member are of circular shape, and wherein the inner width of the edge of the tubular end portion of the stylus of the extractor member and the outer width of the edge of the tubular end portion of the stylus of the punch member are identical.

62. A method of forming an apparatus for forming a tissue array in an at least substantially solid recipient, the method comprising:

- providing an extractor member and a punch member, wherein the extractor member comprises a stylus and a tubular end portion for accommodating a tissue sample, the tubular end portion having an opening, and wherein the punch member comprises a stylus and a tubular end portion for accommodating matter punched from the recipient, the tubular end portion having an opening;

- providing a housing; - arranging a first guiding means in the housing, thereby arranging the stylus of the extractor member relative to the first guiding means to allow the first guiding means to provide fixation to said stylus inside the housing, such that the stylus of the extractor member is movable in the axial direction;

- arranging a second guiding means in the housing, thereby arranging the stylus of the punch member relative to the second guiding means to allow the second guiding means to provide fixation to said stylus inside the housing, such that the stylus of the punch member is movable in the axial direction

- providing a punch actuator;

- arranging the punch actuator such that it is in communication with the punch member; - providing an extractor actuator; and

- arranging the extractor actuator such that it is in communication with the extractor member.

63. The method of claim 62, wherein the stylus of the extractor member is arranged relative to the first guiding means such that stylus of the extractor member is positioned at least partially within the first guiding means.

64. The method of any one of claims 62 or 63 , wherein the stylus of the punch member is arranged relative to the second guiding means such that stylus of the punch member is positioned at least partially within the second guiding means.

65. The method of any one of claims 62 - 64, wherein the stylus of the punch member is arranged to be in communication with the extractor member in a reciprocal relationship, such that movement of the stylus of the punch member in the direction of the tubular end portion thereof effects movement of the stylus of the extractor member in the direction opposite to the tubular end portion of the extractor member and vice versa.

66. The method of any one of claims 62 - 64, wherein the stylus of the punch member is movable in a first and in a second axial direction, the first direction being defined by the orientation of the opening of the tubular end portion of the stylus and the second direction being opposite thereto, the method comprising arranging the stylus of the punch actuator to be in unidirectional communication with the stylus of the extractor member in the second direction, such that movement of the stylus of the punch member in the second direction is imparted to the stylus of the extractor member, whereas movement of the stylus of the punch member in the first direction is not imparted to the stylus of the extractor member.

67. A method of forming a tissue array, comprising:

- providing an apparatus according to any one of claims 1 - 61; - bringing the apparatus into a position where the opening of the tubular end portion of the extractor member is arranged about a tissue;

- moving the tubular end portion of the extractor member in the direction of the opening thereof, thereby inserting the tubular end portion into the tissue,

- moving the stylus of the extractor member in the direction opposite to the opening of the tubular end portion of the extractor member, such that a tissue sample is accommodated in the tubular end portion of the extractor member;

- bringing the apparatus into a position where the opening of the tubular end portion of the punch member is in contact with an at least substantially solid recipient;

- moving the stylus of the punch member in the direction defined by the orientation of the opening of the tubular end portion thereof, thereby inserting the tubular end portion of the punch member into the recipient, such that a portion of the recipient is accommodated in the tubular end portion of the punch member and a cavity is formed in the recipient;

- bringing the apparatus into a position where the opening of the tubular end portion of the extractor member is positioned about the cavity formed in the recipient, such that the tissue sample accommodated in the tubular end portion of the extractor member can be inserted into the cavity;

- releasing the tissue sample accommodated in the tubular end portion of the extractor member from the tubular end portion, thereby inserting the tissue sample into the cavity formed in the recipient.

68. The method of claim 67, wherein the cavity formed in the recipient by inserting the tubular end portion of the punch member therein has a maximal width that corresponds to the maximal outer width of the portion of the tubular end portion of the punch member.

69. The method of claims 67 or 68, wherein moving the stylus of the extractor member in the direction opposite to the opening of the tubular end portion of the extractor member comprises moving the stylus of the extractor member within the tubular end portion of the extractor member.

70. The method of claim 69, wherein moving the stylus of the extractor member in the direction opposite to the tubular end portion of the extractor member comprises generating a negative pressure in the tubular end portion, such that a tissue sample is drawn into the tubular end portion of the extractor member.

71. The method of any one of claims 67 - 71, wherein releasing the tissue sample accommodated in the tubular end portion of the extractor member comprises moving the stylus of the extractor member in the direction defined by the orientation of the opening of the tubular end portion thereof.

72. The method of any one of claims 67 - 71, wherein moving the tubular end portion of the extractor member in the direction defined by the orientation of the opening thereof is achieved by moving the entire apparatus according to any one of claims 1 - 61 in the direction defined by the orientation of the opening of the tubular end portion of the extractor member.

73. The method of claim 72, wherein bringing the apparatus into a position where the opening of the tubular end portion of the extractor member is arranged about a tissue further comprises: arranging the stylus of the extractor member in a predefined position relative to the direction defined by the orientation of the opening of the tubular end portion thereof.

74. The method of claim 73, wherein said predefined position of the stylus of the extractor member is a stop position from where the stylus of the extractor member can only be moved in the direction opposite to the direction defined by the orientation of the opening of the tubular end portion of the extractor member.

75. The method of any one of claims 67 - 74, wherein inserting the tubular end portion of the punch member into the recipient comprises inserting a selected portion of the tubular end portion of the punch member into the recipient.

76. The method of any one of claims 67 - 75, wherein the stylus of the punch member is in communication with the extractor member in a reciprocal relationship, such that movement of the stylus of the punch member in the direction of the opening of the tubular end portion thereof effects movement of the stylus of the extractor member in the direction opposite to the opening of the tubular end portion of the extractor member and vice versa, wherein moving the stylus of the extractor member in the direction opposite to the orientation of the opening of the tubular end portion of the extractor member, after inserting the tubular end portion of the extractor member into the tissue, is achieved by moving the stylus of the punch member in the direction of the opening of the tubular end portion of the same.

77. The method of any one of claims 67 - 76, wherein the stylus of the punch member of the apparatus is movable in a first and in a second axial direction, the first direction being defined by the orientation of the opening of the tubular end portion of the stylus and the second direction being opposite thereto, and wherein the stylus of the punch member is in unidirectional communication with the stylus of the extractor member in the second direction, such that movement of the stylus of the punch member in the second direction is imparted to the stylus of the extractor member, whereas movement of the stylus of the punch member in the first direction is not imparted to the stylus of the extractor member, and wherein moving the stylus of the extractor member in the direction opposite to the orientation of the opening of the tubular end portion of the extractor member, after inserting the tubular end portion of the extractor member into the tissue, is achieved by moving the punch member in the second direction.

78. The method of claims 76 or 77, wherein the stylus of the punch member is in communication with the stylus of the extractor member and wherein the communication is releasable.

79. The method of any one of claims 67 - 78, further comprising arresting the stylus of the extractor member once the tissue sample is accommodated in the tubular end portion of the extractor member.

80. The method of claim 79, wherein arresting the extractor member further comprises arresting the punch member.

81. The method of claim 80, wherein the stylus of the punch member is in communication with the stylus of the extractor member, the communication being releasable, and wherein the communication of the styli is released once the punch actuator is arrested.

82. The method of claim 81 , wherein the communication of the stylus of the punch member with the stylus of the extractor member is reversibly releasable and wherein the communication is re-established once the tissue sample is released from the tubular end portion of the extractor member.

83. The method of any one of claims 67 - 82, wherein the punch member further comprises an ejector and wherein operating the ejector causes the portion of the recipient accommodated in the tubular end portion of the stylus of the punch member to be released.

84. The method of claim 83, wherein the ejector is a rod that is movable into and/or within the tubular end portion of the stylus of the punch member.

85. A kit for forming a tissue array, the kit comprising an apparatus according to any one of claims 1 - 61 and an at least substantially solid recipient.