Abstract:
Embodiments of the invention relate to a biological sample holder and for holding biological samples. Conventionally, processing of biological samples, which may be stored on a biological sample storage medium, is done manually with samples being tested individually. However, handling of the samples is difficult and time consuming; greater demand for storage and extraction of genetic material has led to a requirement for greater throughput. In embodiments of the present invention, there is provided a biological sample holder comprising a chamber holding a biological sample storage medium, the chamber comprising one or more openings for receiving a liquid when inserted therein. This provides a means of holding a biological sample which is easy to handle and suitable for automation, for example in an array of such holders, allowing processing of multiple biological samples in parallel.

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention relates to a biological sample holder and to a method of assembling same. 
       BACKGROUND OF THE INVENTION 
       [0002]    Biological samples, such as blood samples taken for drug discovery and saliva taken for DNA profiling in criminal investigations, are typically held in an absorbent storage medium, which may comprise a membrane impregnated with chemicals for stabilising the sample. The samples are allowed to dry and, once dry, the biological storage medium can be transported to a testing facility for analysis. 
         [0003]    Typically, when testing the sample, small pieces of the sample holding membrane are punched out. These pieces are small enough to minimise wasteful consumption of the sample but large enough to be handled and also to contain enough biological material for the test to be carried out successfully. The membrane may be made from a variety of materials, such as paper, glass fiber, polyester, polyether sulfone (PES), polyamide (Nylon), polypropylene, polytetrafluoroethylene (PTFE), polycarbonate, cellulose nitrate, cellulose acetate and aluminium oxide. 
         [0004]    Conventionally, this processing is done manually and samples are tested individually. However, greater demand for storage and extraction of genetic material has led to a requirement for greater throughput; the standard is now hundreds or thousands of extractions per day. Currently, matrix-based solutions for storage of biological samples such as nucleic acid are limited in this respect because automated or multiple-sample processing of the samples is not compatible with the storage medium. 
         [0005]    It is an object of the present invention to mitigate the limitations associated with storing biological samples such as nucleic acids and proteins in matrices and provide a way to increase the speed and efficiency of sample processing. 
       SUMMARY OF THE INVENTION 
       [0006]    In accordance with a first aspect of the present invention, there is provided a biological sample holder, comprising:
       an upper portion;   a chamber extending from said upper portion, the chamber having a first end and a second end, the first end adjoining the upper portion and the second end opposing the first end;   a biological sample storage medium in the chamber;   a first retaining means, the first retaining means being located at the first end of the chamber and being for inhibiting the biological sample storage medium from moving out of said chamber through the first end of the chamber; and   a second retaining means, the second retaining means being located at said second end of the chamber and being for inhibiting the biological sample storage medium from moving out of said chamber through the second end of the chamber,   wherein the chamber has at least one internal dimension larger than a corresponding dimension of the biological sample storage medium, whereby the biological sample storage medium can move within the chamber between the first retaining means and the second retaining means,   wherein the chamber comprises one or more openings, whereby the chamber can receive a liquid when inserted therein, so that the biological sample storage medium comes into contact with the liquid.       
 
         [0014]    This provides a means by which a biological sample, which may be held on the biological sample storage means can be easily handled. The biological sample holder is easy to assemble, because the biological sample storage means is held in place between two retaining means, between which it may move, which avoids any necessity for precise positioning of the biological sample storage medium and/or the retaining means during assembly. 
         [0015]    Preferably, the one or more openings comprise one or more holes and/or slits in a side wall of the chamber. This enables the chamber to receive a liquid without the biological sample storage medium being forced up against the first retaining means, which may inhibit flow of liquid through the biological sample storage medium. 
         [0016]    The first retaining means may comprise one or more holes and/or one or more cavities. This further improves the flow of liquid through the biological sample storage medium. This feature may be particularly useful when openings are not provided in a side wall of the chamber. 
         [0017]    The first retaining means may comprise a stopper held in biological sample holder by an interference fit. The second retaining means may comprise a tapered portion, the tapered portion having a cross-sectional dimension smaller than a corresponding cross-sectional dimension of the biological sample storage medium. In some embodiments, the second end is closed, and said second retaining means comprises said closed end. 
         [0018]    In some embodiments, the biological sample holder according to the invention comprises a stake, and the biological sample storage medium is located on said stake. This provides a convenient means for locating the biological sample storage medium, preventing excessive movement of same. 
         [0019]    The biological sample storage medium comprises a membrane for absorbing liquid biological samples and/or a matrix disc. The biological sample storage medium may be of a paper material. 
         [0020]    In some embodiments, the upper portion and a wall of the chamber are of a plastics material, and are formed from a single mould. This provides a convenient process for use in manufacturing the biological sample holder. 
         [0021]    Preferably, the biological sample holder comprises a seal for forming a seal between the biological sample holder and a well when said biological sample holder is inserted into said well. This can help prevent evaporation of a liquid contained in the well during processing of a biological sample. 
         [0022]    The biological sample holder may be suitable for insertion into a polymerase chain reaction (PCR) tray. 
         [0023]    In accordance with a second aspect of the present invention, there is provided a biological sample holder comprising a chamber containing a biological sample storage medium, the chamber having first and second spaced apart retainers defining a space for holding the biological sample storage medium and within which the biological sample storage medium is moveable, and one or more openings between the retainers for allowing liquid to enter the chamber, so that the liquid comes into contact with the biological sample storage medium 
         [0024]    In accordance with a third aspect of the present invention, there is provided an array of biological sample holders according to the first aspect, in which the array is supported on a base plate. This enables multiple biological samples to be processed in parallel. 
         [0025]    The array may comprise at least one asymmetric feature located on an outside edge of the base plate. The array may comprise a grid-coordinate system to identify each of the biological sample holders of the array. 
         [0026]    Preferably, the array comprises a gasket on the base plate around each of the stakes. This may inhibit or prevent evaporation and/or spillage losses during processing of a biological sample. 
         [0027]    The array may comprise a computer readable tag. 
         [0028]    In accordance with a fourth aspect of the present invention, there is provided an apparatus for storing and processing in parallel plural biological samples, the apparatus comprising: 
         [0029]    an array of biological sample holders according to the second aspect; and 
         [0030]    a tray comprising an array of wells, 
         [0031]    wherein the position of the wells corresponds to the position of the biological sample holders in said array, and the depth and diameter of the wells exceeds the length and diameter of the biological sample holders in said array. 
         [0032]    The tray may comprise a polymerase chain reaction (PCR) tray. 
         [0033]    In accordance with a fifth aspect of the present invention, there is provided a kit of parts for assembling a biological sample holder, the kit comprising: 
         [0034]    a receptacle comprising a tubular portion, the tubular portion having an aperture at one end, a first retaining means for retaining a biological sample storage medium at an opposite end, and one or more openings in a side wall of the tubular portion; 
         [0035]    a biological sample storage medium for insertion into the receptacle; 
         [0036]    a second retaining means insertable into the receptacle via the aperture, the second retaining means being fixable in the tubular portion at a position such that the one or more openings are located between the first retaining means and the second retaining means, thereby forming a chamber between the first and second retainers for retaining a biological sample storage medium in the chamber. 
         [0037]    In accordance with a sixth aspect of the present invention, there is provided a method of assembling a biological sample holder, comprising: 
         [0038]    providing a receptacle, the receptacle comprising a tubular portion having a first retaining means at a first end and an aperture at a second end, the second end opposing the first end; 
         [0039]    providing a biological sample storage medium, the biological sample storage medium having a cross-sectional dimension smaller than a corresponding internal cross-sectional dimension of the tubular portion; 
         [0040]    inserting the biological sample storage medium into the receptacle through the aperture, whereby the biological sample storage medium moves through the tubular portion towards the first end; 
         [0041]    inserting a second retaining means into the receptacle through the aperture and fixing said second retaining means in said tubular portion, thereby forming a chamber between the first retaining means and the second retaining means, the first retaining means and the second retaining means inhibiting the biological sample storage medium from moving out of the chamber, 
         [0042]    wherein the chamber has at least one internal dimension larger than a corresponding dimension of the biological sample storage medium, whereby the biological sample storage medium can move within the chamber between the first retaining means and the second retaining means, 
         [0043]    wherein the chamber comprises one or more openings, whereby the chamber can receive a liquid when inserted therein, so that the biological sample storage medium comes into contact with the liquid. 
         [0044]    Preferably, the one or more openings are located in a side wall of the of the tubular portion and the method comprises fixing the second retaining means at a position such that the openings are located between the first retaining means and the second retaining means. 
         [0045]    A method according to any preceding claim, comprising fitting said first retaining means using an interference fit. The tubular portion may be tapered to facilitate the interference fit. 
         [0046]    A seventh aspect of the present invention provides the use of a biological sample holder according to the first aspect or second aspect, an array according to the third aspect, or apparatus according to the fourth aspect, for storing and/or processing a biological sample. 
         [0047]    Other aspects of the invention are provided in the claims. 
         [0048]    Further features and advantages of the invention will become apparent from the following description of illustrative embodiments of the invention, given by way of example only, which is made with reference to the accompanying drawings. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0049]      FIG. 1   a  shows an exploded side view of a biological sample holder according to a first embodiment of the present invention; 
           [0050]      FIG. 1   b  shows an exploded cross-sectional view of a biological sample holder according to the first embodiment of the present invention; 
           [0051]      FIG. 2   a  shows a cross-sectional side view of a biological sample holder according to the first embodiment of the present invention; 
           [0052]      FIG. 2   b  shows a perspective cross-section views of a biological sample holder according to the first embodiment of the present invention; 
           [0053]      FIG. 3   a  shows a perspective view of an array of biological sample holders according to a second embodiment of the present invention; 
           [0054]      FIG. 3   b  shows an exploded perspective view of an array of biological sample holders according to a third embodiment of the present invention; 
           [0055]      FIG. 3   c  shows an exploded perspective view of a PCR tray corresponding with an array of biological sample holders according to a fourth embodiment of the present invention; 
           [0056]      FIG. 3   d  shows a cross-section view of a PCR well and a biological sample holder according to the first embodiment inserted therein; 
           [0057]      FIG. 4  shows a cross-section view of the edge of the base plate of an array of devices for holding discs of biological sample holding membrane according to a fifth embodiment of the present invention; 
           [0058]      FIG. 5  shows a perspective view of an array of biological sample holders comprising a gasket according to a sixth embodiment of the present invention; 
           [0059]      FIG. 6  shows a plan view of the base plate of an array of biological sample holders comprising a grid-coordinate reference system according to a seventh embodiment of the present invention; 
           [0060]      FIG. 7  shows a side aspect of an array of biological sample holders comprising a computer readable tag coded with identification data according to an eighth embodiment of the present invention; 
           [0061]      FIG. 8  shows a plan view of an array of biological storage devices, wherein the base plate of the array comprises an asymmetric external geometry according to an ninth embodiment of the present invention; 
           [0062]      FIG. 9   a  shows an exploded perspective view of a biological sample holder according to a tenth embodiment of the present invention; 
           [0063]      FIG. 9   b  shows a cross-sectional view of a biological sample holder according to the tenth embodiment of the present invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0064]      FIGS. 1   a  and  1   b  show, respectively, an exploded side view and an exploded perspective cross-sectional view of a biological sample holder  10  according to an embodiment of the present invention.  FIGS. 2   a  and  2   b  show, respectively, cross-sectional side view and a perspective side-view of a perspective view of a biological sample holder  10  in assembled form according to the first embodiment. Longitudinal and transverse axes are defined by the arrows in  FIGS. 1   a,    1   b,    2   a  and  2   b,  labelled L and T respectively. 
         [0065]    The biological sample holder  10  comprises a receptacle  12 , a biological sample storage medium in the form of a matrix disc  14  and a retaining means in the form of a stopper  16 . The receptacle  12  is hollow and comprises an upper portion  18 , a lower portion  20  and a hollow tubular section in the form of a barrel  24  extending through the upper portion  18  to the lower portion  20 . The upper portion  18  comprises a base portion  22  and a seal  26  arranged around the circumference of the barrel  24  where the latter joins the base portion  22 . The barrel  24  extends through the base portion  22 , thereby forming an aperture  25 , at the top end of the receptacle  12   a.  There are one or more openings in the form of holes  22   a  in the side walls of the lower portion  20  and holes  22   b  in the tip end  21  of the lower portion  20 . 
         [0066]    The receptacle  12  is typically approximately 20 mm in length, of which the chamber  20  may occupy approximately 5 mm. The aperture  25  is typically approximately 4 mm in diameter. The walls of the barrel typically have a thickness of approximately 0.4 mm. The barrel  24  may have the same internal diameter along its length, or it may taper towards the lower portion  20 . The lower portion  20  may similarly have parallel or tapered sides. In the present embodiment, the barrel  24  and the lower portion  20  have circular transverse cross-sections; however, in some embodiments one or both of the barrel  24  and the lower portion  24  have other transverse cross-sections, for example elliptical or square cross-sections. The walls of the barrel  12  and the lower portion  20 , and or/the base  22  may be made from a chemically and biologically inert material that can withstand a temperature of 95° C. Suitable materials include polycarbonate, polystyrene, or polypropylene. The seal  26  may be made from silicon or a silicon based compound. 
         [0067]    The matrix disc  14  may be substantially flat and circular, and/or may comprise a membrane, suitable for holding dried biological material, such as a blood sample. The matrix disc  14  may be made of a paper material, such as FTA® elute paper. The matrix disc  14  is arranged to have one or more dimensions smaller than the internal dimensions of the lower portion  20 . For example, the matrix disc  14  may have a transverse cross-sectional dimension smaller than a corresponding cross-sectional dimension of the lower portion. Typically, the matrix disc  14  has a diameter of approximately 3 mm and a thickness of approximately 1 mm. 
         [0068]    The stopper  16  is typically made of a rubber or plastics material that can withstand a temperature of 95° C., and has a transverse cross-section arranged to correspond to a transverse cross-section of the barrel  24  so that it can be fitted therein by an interference fit. 
         [0069]    The receptacle  12 , the matrix disc  14  and the stopper  16  may be provided as an unassembled kit of parts for forming a biological sample holder. During assembly, the matrix disc  14  is typically formed by punching the matrix disc  14  from a larger sheet of matrix material. The matrix disc  14  is typically infused with a biological sample, such as a blood or saliva sample, prior to insertion into the receptacle  12 , though in some cases the biological sample may be added after the matrix disc  14  after insertion into the receptacle  12 . 
         [0070]    The matrix disc  14  is inserted into the receptacle  12  via the aperture  25 . Because the matrix disc  14  is arranged to have a transverse cross-sectional dimensions (for example, an external diameter) smaller than a corresponding cross-sectional dimension (for example, an internal diameter) of the barrel  24 , the matrix disc  14  can be inserted into the receptacle  12  by simply dropping the matrix disc  14  through the aperture  25  and allowing it to fall through the barrel  24  to the lower portion  20 . The stopper  16  is subsequently inserted through the aperture  25  and fitted into the barrel  24  by an interference fit; as mentioned above, the barrel  24  may be tapered towards the lower portion  20  to facilitate the interference-fitting. The lower portion  20  effectively forms a chamber, bounded by the stopper  16  at one end, and the tip end  21  of the lower portion  20  at another, opposing, end. 
         [0071]    The assembly steps described above thus may be performed entirely manually, or partially or wholly automatically. 
         [0072]    Once the biological sample holder  12  has been assembled, the matrix disc  14  is held in the chamber formed in the lower portion  20 , as shown in  FIGS. 2   a  and  2   b . The matrix disc  14  is inhibited or prevented from moving out of the chamber through the tip end  21  by a retaining means  28   a.  In the embodiment shown in  FIGS. 1   a  to  2   b,  the retaining means  28   a  takes the form of a set of transverse bars formed across the tip end  21  of the chamber. In other embodiments, other retaining means may be used; for example, the tip end  21  may be closed, the closed end itself forming the retaining means, or a tapered portion of the tip end  21  may form the retaining means. 
         [0073]    The matrix disc  14  is prevented from moving out of the chamber through the end of the chamber opposing the tip end  21  by the stopper  26 . Because at least one dimension of the matrix disc  14  is smaller than a corresponding dimension of the lower portion  20 , the matrix disc  14  is free to move between the stopper  16  and the retaining means  28   a.    
         [0074]    The biological sample holder  10  is thus simple to manufacture, in a way that avoids any difficult procedures that may be required to clamp or otherwise fix the matrix disc  14  and/or stopper  16  at a precisely defined position. 
         [0075]    In a further embodiment according to the present invention, depicted in  FIG. 3   a , a plurality of biological sample holders  10  are arranged to form an array  30  such that multiple samples may be processed in a single step. The holders may be as shown and described above with reference to  FIGS. 1   a,    1   b,    2   a  and  2   b.  Each of the biological sample holders  10  are physically connected at the base portion  12  to a base plate  31 . 
         [0076]    The biological sample holders  10  and the base plate  31  may be manufactured as separate parts as shown in  FIG. 3   b . This allows flexibility in the design of the array  30  and, in particular, in the number of biological samples holders  10  that form the array  30 . The biological sample holders  10  may be moulded individually or in rows  32 , for example, and the base plate may simply be formed with an array of holes  33  into which the base portions  11  of the biological sample holders  10  sit. The biological sample holders  10  may be fixed to the base plate  31  by an ultrasonic weld or any other suitable method. 
         [0077]    In one embodiment, the array  30  of biological sample holders  10  and the base plate  31  are manufactured by injection moulding as a single component. In this embodiment, the holes  22   a  in the side walls of the lower portion  20  may be formed by pins inserted through the mould during the injection moulding process, the pins being removed prior to the array  30  and base plate  31  being removed from the mould. 
         [0078]    The dimensions of the base plate  31  and the positions of the biological sample holders  10  on the base plate  31  are chosen to correspond with the dimensions and positions of wells in a tray of wells. In this example the tray is a polymerase chain reaction (PCR) type tray  34  and the positions of wells  35  within the PCR tray  34  may be as shown in  FIG. 3   c . Typically, the wells  35  in the PCR tray  34  will be at least partially filled with a liquid, such as an elution liquid  36  for elution of nucleic acid. In the arrangement shown in  FIGS. 3   a ,  3   b  and  3   c , the biological sample holders  10  form an 8×12 rectangular array, however, it will be appreciated that any other one- or two-dimensional arrangement corresponding to an equivalent arrangement of wells  35  in a PCR tray  34  is possible. In a preferred embodiment according to the present invention, the external dimensions of the base plate  31  correspond to the SBS standard laboratory footprint such that the array  30  may be handled by standard laboratory material handling equipment. Typically, the base plate is 127.76 mm long and 85.48 mm wide. 
         [0079]    As shown in  FIG. 3   d , the central longitudinal axis of the biological sample holder  10  is arranged to be substantially parallel to the central longitudinal axis of the PCR well  35 . Further, the diameter of at least the lower portion  20  of the biological sample holder  10  is arranged to be smaller than an internal diameter of the PCR well  35 , and the height of the biological sample holder  10  is arranged such that when the base plate  31  of the array  30  is attached to the PCR tray  34 , the lower portion  20  of the biological sample holders  10  reaches far enough into to the well  35  that it is inserted into, and immersed in, the elution liquid  36  contained in the well, without coming into physical contact with the internal walls of the PCR well  35 . 
         [0080]    On insertion into the elution liquid  36 , the chamber formed in the lower portion  20  of the receptacle  12  can receive the elution liquid  36  via the holes  22   a  and  22   b,  so that the elution liquid  36  enters the chamber and comes into contact with the matrix disc  14  held in the chamber, and with any biological sample held on the matrix disc  14 . The seal  26  engages with the walls of the well, forming a seal which inhibits evaporation of the elution liquid  36  during processing. 
         [0081]    As mentioned above, the matrix disc  14  is free to move within the chamber formed in the lower portion  20  of the receptacle  12 . The holes  22   a  formed in the side wall of the lower portion  20  enable the elution liquid  36  to be received therein, without the matrix disc  14  being forced upwards and becoming attached to the stopper  16 . The holes  22   a  in the side walls thus allow the matrix disc  14  to remain mobile in the elution liquid  36  when the lower portion  20  is inserted therein, improving the flow of elution liquid  36  through the matrix disc  20 , thereby improving the efficiency of the processing. 
         [0082]    Although not shown in the figures, the stopper  16  may also include one or more holes or cavities. This may be particularly useful in cases in which the lower portion  20  has holes  22   b  at the tip end  21 , but does not have any holes  22   a  in the side wall; even if the matrix disc  14  is forced upwards and becomes attached to the stopper  16 , the holes or cavities in the stopper  14  enable flow of the elution liquid  16  through the matrix disc  16 . 
         [0083]    It will be appreciated that biological sample holders  10  according to embodiments of the present invention may be inserted into wells  35  for processing individually, or as part of a one- or two-dimensional array, as described above. Further, a biological sample holder  10  may be processed through multiple processing steps, in which the biological sample holder  10  is inserted into and removed from multiple wells  35 , which may each contain a different liquid. It will be further appreciated that whilst biological sample holders  10  according to embodiments of the present invention are particularly suitable for automatic processing, they may also be used for manual processing. 
         [0084]      FIG. 4  shows, in cross-section, a further embodiment of the present invention in which the external edges of the base plate  31  of the array  30  form a mechanical clip  41  to hold the array  30  in place on the PCR tray  34 . The edge of the PCR tray  34  is shown in contact with the base plate  31  of the array  30 . The PCR tray  34  has a corresponding protrusion  42  at its edge, which binds with the clip  41 . The dimensions of the clip  41  are such that it is flexible enough that the base plate  31  may be attached to and removed from the PCR tray  34  by application of appropriately directed forces, but stiff enough that there is negligible movement of the base plate  31  relative to the PCR tray  34  when the two components are connected and such that the base plate  31  cannot detach from the PCR tray  34  inadvertently when the combined components are gripped solely by the edges of the base plate  31 , either by a human operator or a mechanical handling system. 
         [0085]    In a further embodiment according to the present invention, as shown in  FIG. 5 , rather than each individual biological sample holder  10  having a seal  26 , the array  30  is provided with a gasket  51  fixed to the base plate  31  and surrounding each of the biological sample holders  10 . The gasket  51  is manufactured from an impermeable material and is of sufficient thickness and flexibility to form a suitable seal between the base plate  31  of the array  30  and the PCR tray  34  to minimise loss of the elution liquid  36  by evaporation or spillage. 
         [0086]      FIG. 6  shows an embodiment according to the present invention wherein the base plate  31  comprises identifying grid-coordinates  61  correlating with the positions of each of the biological sample holders  10 , to enable identification and addressing of individual samples. 
         [0087]      FIG. 7  shows a further embodiment according to the present invention wherein the base plate  31  comprises a identification tag  71  comprising coded computer readable identification information. In an embodiment, the tag  71  comprises a barcode  72  that can be scanned and compared with a database of sample identification codes; other types of tag may be used, for example an RFID tag. 
         [0088]    In a further embodiment according to the present invention, as shown in  FIG. 8 , the base plate  31  comprises an asymmetric geometry such that the array  30  can only couple with the PCR tray  34  in a single orientation. In the embodiment shown, this is achieved by incorporating a bevel  81  in one of the four corners of the base plate  31  and corresponding PCR tray  34 . However, it will be apparent that other geometries will also achieve the same result. 
         [0089]    The biological sample holders  10  and the array  30  described by the above embodiments may be used in any process whereby a liquid sample is stored in dried form within a matrix material and then subsequently removed from the matrix material by elution. A typical process compatible with DNA amplification techniques may involve the following steps: inserting the one or more biological sample holders  10  in the wells of a tray with each well having a volume of at least 800 μL so that each matrix is immersed in 500 μL of water. Transferring the one or more biological sample holders  10  to a PCR tray  34  that contains 30 μL of water in each well  35 ; transferring the array  30  and PCR tray  34 , together, to a thermal cycler and heating to 95° C. for thirty minutes; pulse vortexing the array  30  and PCR tray  34 , together, sixty times; spinning the array  30  and PCR tray  34 , together, in a centrifuge for thirty seconds at 1000×g; removing the array  30  from the PCR tray  34 ; and passing the PCR tray  34  on to be analysed. 
         [0090]      FIGS. 9   a  and  9   b  show, respectively, an exploded perspective view and a cross-sectional view of a biological sample holder  50  according to an alternative embodiment of the present invention; transverse and longitudinal axes are defined by the arrows in  FIGS. 9   a  and  9   b , labelled L and T respectively. The biological sample holder  90  of this embodiment comprises a receptacle  92  and a matrix disc  54 . The receptacle  92  includes an upper portion  96  and a lower portion  98 . The upper portion  96  includes a base portion  100 , a stem portion  102  and a seal  104  arranged around the circumference of the stem portion  102  where the latter joins the base portion  100 . The side walls of the lower portion  98  are provided with holes  106   a  and  106   b.  The receptacle  92  is provided with a stake  108 , which typically extends from the step portion  102  to the tip end  93  of the receptacle  92 . The stake  108  may have a pointed tip portion  108   a.  The walls of the lower portion  98  include protrusions, herein referred to as “fingers”  110  which extend downwards towards the tip end  93  of the receptacle  92 . The fingers  70  taper inwards towards the tip end  93 . 
         [0091]    In the present embodiment, the stem portion  102  and the lower portion  98  have circular transverse cross-sections; however, in some embodiments one or both of the barrel and the chamber have other transverse cross-sections, for example elliptical or square cross-sections. The receptacle  92  may be made from a chemically and biologically inert material that can withstand a temperature of 95° C. Suitable materials include polycarbonate, polystyrene, or polypropylene. The seal  104  may be made from silicon or a silicon based compound. 
         [0092]    The matrix disc  94  is provided with a hole  112 , which is arranged to be sufficiently large to fit over the tip portion  108   a  of the stake  108 . The matrix disc  94  may be otherwise similar to or the same as the matrix disc  14  described above with reference to  FIGS. 1   a,    1   b,    2   a  and  2   b,  and may similarly be formed by punching the matrix disc  94  from a larger sheet of matrix material. 
         [0093]    The internal diameter of the hole  112  is typically approximately 1 mm The hole  112  may be cut by the tip portion  108   a  of the stake  108 , or by some other means. Once the hole is cut, the matrix disc  94  is fitted onto the tip portion  108   a  of the stake  108 . 
         [0094]    Once the biological sample holder  90  has been assembled, as shown in  FIG. 9   b , the matrix disc  94  is located in the lower portion  98  located on the stake  108 . The matrix disc  94  may be loose-fitted on to the tip portion  108   a  of the stake  108 , so that the matrix disc may move longitudinally along the tip portion  108   a.  The matrix disc  94  is arranged to have a transverse cross-section having a dimension larger than a corresponding dimension of a transverse cross-section formed by the tips of the fingers  110 , so that the fingers  110  act as a retaining means, inhibiting or preventing the matrix disc  54  from moving out of the lower portion  98  through the tip end  93 . The stake  108  includes a step portion  108   b  having a diameter larger than that of the tip portion  108   a.  The hole  112  in the matrix disc  94  is arranged to have a diameter smaller than that of the step portion  108   b,  so that the step portion  108   b  acts as a retaining means, inhibiting or preventing the matrix disc  94  from moving out of the lower portion  98  into the upper portion  96  of the receptacle  92 . The lower portion  98  thus forms a chamber in which the matrix disc  94  can move longitudinally between retaining means at opposing ends of the chamber inhibiting or preventing the matrix disc  94  from moving out of the chamber. 
         [0095]    It will be appreciated that the biological sample holder  90  described above with reference to  FIGS. 9   a  and  9   b  can be used to process a biological sample in the same or a similar way as was described above in relation to the biological sample holder  10  of  FIGS. 1   a,    1   b,    2   a  and  2   b.  An array of biological sample holders  90  may also be provided, in the same or a similar way as was described in relation to the biological sample holder  10  of  FIGS. 1   a,    1   b,    2   a  and  2   b.    
         [0096]    When the biological sample holder  90  is inserted into a well  35 , with the lower portion being inserted into a liquid  36  contained in the well  35 , the liquid can enter into the lower portion  98  via the holes  106   a  and slits  106   b  in the lower portion, and through the tip end  93 . In the embodiment shown, the upper portion also includes holes  106   c  in the side wall, and the liquid may also enter through these holes. The liquid  36  thus received in the lower portion  98  comes into contact with the matrix disc  94  and any biological sample held thereon, allowing processing of the latter. 
         [0097]    In the embodiment shown, the boundary between the lower portion  98  and the upper portion  96  of the receptacle  92  is formed by the step portion  108   b  of the stake  108 , which, as explained above, acts as a retaining means, inhibiting or preventing the matrix disc from moving to the upper portion  96  of the receptacle  92 . This retaining means which forms the boundary between the lower portion  98  and the upper portion may take other forms, for example it may take the form of a ring protruding from the stake  108 ; in some embodiments, the stake has substantially the same cross-sectional dimensions along its whole length, and the boundary between the lower portion  98  and the upper portion  96  is defined by the location where the stake  108  meets the stem portion  102 , with the latter acting as a retaining means inhibiting or preventing matrix disc  94  from moving into the upper portion  96 . 
         [0098]    The above embodiments are to be understood as illustrative examples of the invention. Further embodiments of the invention are envisaged. For example, although in the biological sample holder  10  described above in relation to  FIGS. 1   a,    1   b,    2   a  and  2   b,  the chamber within which the matrix disc  14  is held is described as being located in a “lower portion”  20 , which is located at an end of the receptacle  12 , in some embodiments the chamber is not located at and end of the receptacle; instead, the chamber may be located in a mid-section of the receptacle, for example. Further, in the above examples, the stopper  16  was interference fitted in the barrel  24 ; however, in some examples it may be fitted using an adhesive, notches and/or protrusions in the barrel  24  wall and the stopper  16 , or some other means. Furthermore, equivalents and modifications not described above may also be employed without departing from the scope of the invention, which is defined in the accompanying claims.