Abstract:
Embodiments of the invention provide a bioreactor chamber assembly comprising: a bioreactor chamber comprising first and second portions arranged to be coupled to one another thereby to provide a liquid-tight seal therebetween; a pair of clamp members; and a pair of resilient loop elements, wherein the clamp members are arranged to sandwich the chamber between the clamp members and the loop elements are arranged to apply a force between the clamp members to urge the first and second portions together.

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention relates to chambers for bioreactors. 
       BACKGROUND 
       [0002]    It is known to provide a bioreactor having a culture chamber and means for passing a flow of culture medium through the chamber in order to enable a wide range of studies of biological materials. By way of example, the biological material under investigation may be a monolayer cell culture, scaffold culture or tissue slice. WO2005/123258 discloses a bioreactor for studying the effects of imposed stimuli on cellular activity. 
       STATEMENT OF THE INVENTION 
       [0003]    In a first aspect of the invention there is provided a bioreactor chamber assembly comprising:
       a bioreactor chamber comprising first and second portions arranged to be coupled to one another thereby to provide a liquid-tight seal therebetween;   a pair of clamp members; and   a pair of resilient loop elements,   wherein the clamp members are arranged to sandwich the chamber between the clamp members and the loop elements are arranged to apply a force between the clamp members to urge the first and second portions together.       
 
         [0008]    This has the advantage that the first and second portions may be clamped together in a rapid, convenient and reliable manner. 
         [0009]    Preferably each loop element is arranged to apply a force to each clamp member at a different respective position of each clamp member such that each loop element applies a substantially equal and opposite torque to each clamp member about an axis normal to a direction along which the force is applied between the clamp members. 
         [0010]    Preferably the clamp members are each provided with a recessed portion arranged to receive a portion of the chamber therein. 
         [0011]    Preferably the clamp members each comprise a substantially plate-like member. 
         [0012]    The clamp members may be provided with one or more grip portions arranged to constrain movement of the loop elements with respect to the clamp members when the loop elements apply said force between the clamp members. 
         [0013]    Preferably the one or more grip portions each comprise a grooved portion of a clamp member. 
         [0014]    Preferably the one or more grip portions are provided on a side of a clamp member opposite the side on which the chamber is provided. 
         [0015]    Preferably at least one clamp member comprises a substantially disc-shaped member. 
         [0016]    The loop elements may each comprise an endless loop. 
         [0017]    Optionally a pair of loop elements are provided by a single endless loop. In such an embodiment the single endless loop may be provided in a figure of 8 form. One clamp member may be adapted to accommodate a cross-over of the figure of 8 form. 
         [0018]    The loop elements may be formed from an elastomeric material. 
         [0019]    Preferably at least one of the clamp members is fixedly attached to a substrate. 
         [0020]    Preferably at least one of the clamp members is provided by a substrate. 
         [0021]    Preferably the substrate provides a clamp member of a plurality of chamber assemblies. 
         [0022]    Preferably the first portion is a body portion of the chamber, the body portion having at least one open end, and the second portion is a basal portion of the chamber, the basal portion being arranged to provide a closure member for the at least one open end of the body portion. 
         [0023]    Preferably the body portion has a pair of open ends, one end of the body portion being coupled to the basal portion, the opposite end being coupled to a third portion. 
         [0024]    The third portion may have one open end and one closed end. 
         [0025]    Preferably the first and second portions are comprised by a plurality of portions arranged to be coupled together to form the chamber, the chamber being arranged whereby one or more barriers may be provided within the chamber thereby to define a plurality of fluid reservoirs, at least one portion of the chamber having a fluid inlet aperture and a fluid outlet aperture arranged whereby fluid flow through a reservoir may be established. 
         [0026]    Each reservoir may be associated with a different respective portion. 
         [0027]    The one or more barriers may be provided at a location or respective locations substantially between a pair of adjacent portions. 
         [0028]    Preferably the one or more barriers is/are provided in the form of a substantially flat sheet of material, optionally a membrane. 
         [0029]    The one or more barriers may be arranged to allow passage of a prescribed substance therethrough. 
         [0030]    The one or more barriers may be arranged to allow passage of a prescribed substance therethrough wherein the substance is selected from amongst a fluid; a chemical compound, moiety or element; an ion; and a biological material. 
         [0031]    Preferably the fluid inlet aperture of at least one portion is arranged such that fluid entering a reservoir of the chamber through the inlet aperture flows in a direction substantially parallel to a plane of a barrier defining a boundary of the reservoir. 
         [0032]    Preferably the respective portions have substantially the same cross-sectional area as one another. 
         [0033]    Preferably respective portions are provided with one or more respective complementary formations arranged whereby the portions may be coupled to one another, the complementary formations comprising a resiliently deformable material and arranged whereby a liquid-tight seal may be formed between the respective formations without a requirement for a separate seal element. 
         [0034]    This has the advantage that because a separate seal element (such as an ‘O’ ring or any other seal element) is not required, assembly of a module may be made in a more rapid and convenient manner. Furthermore, a component count of a chamber may be reduced thereby simplifying manufacture and assembly. 
         [0035]    In addition, a compatibility of a seal element with liquid or other fluid in a chamber does not need to be verified. Thus, a usefulness of the chamber may be enhanced. A possibility of contamination of a content of a chamber due to an influence of a seal element is thereby eliminated. 
         [0036]    Preferably the one or more formations of the first portion comprise a rim of an end of a wall of the first portion, the rim having a recess formed in a radially inner circumferential portion of the rim whereby the remaining portion of the rim defines a substantially circumferential skirt portion. 
         [0037]    Preferably a corresponding one or more formations of the second portion comprise a corresponding portion of a rim of an end of a wall of said second portion, the wall having a recess formed in a radially outer circumferential portion whereby the remaining portion of the wall defines a skirt portion having a shape and size complementary to that of the skirt portion of the first portion. 
         [0038]    The first and second portions may be arranged to allow a membrane to be coupled between them by entrapment of a portion of the membrane between respective adjacent rims of the first and second portions. 
         [0039]    The chamber may be arranged whereby entrapment of a membrane may be effected when adjacent portions are coupled to one another. 
         [0040]    The portions may be releasably coupled to one another. 
         [0041]    The fluid inlet aperture and fluid outlet aperture of the at least one portion may be provided at substantially opposite locations of the wall of the chamber. 
         [0042]    The chamber may be substantially cylindrical in shape. 
         [0043]    Preferably each portion of the chamber is substantially cylindrical in shape, the portions being arranged to be coupled together in a substantially coaxial configuration. 
         [0044]    Preferably the inlet aperture and the outlet aperture are provided at diametrically opposite locations of each portion. 
         [0045]    Preferably the chamber comprises a portion not having a fluid inlet aperture or a fluid outlet aperture. 
         [0046]    Preferably the assembly is further provided with a sample support arranged to support a sample in the form of a membrane, the support being arranged to allow each of a pair of opposed major faces of the membrane to be exposed to fluid contained within the chamber. 
         [0047]    Preferably the sample support comprises at least one support member arranged to contact a portion of the sample. 
         [0048]    The at least one support member may comprise a ridged element, the ridged element being elongate in a substantially lateral direction thereby to provide an elongate surface upon which a sample may be placed. 
         [0049]    Preferably the at least one support member comprises at least one post element. 
         [0050]    Preferably the at least one post element is provided with an upper surface arranged to contact a sample, the upper surface being one selected from amongst substantially flat, substantially curved and substantially domed. 
         [0051]    The at least one support member may comprise an element substantially in the form of a hemisphere or portion thereof. 
         [0052]    Preferably the sample support comprises a plurality of support members each support member being arranged to contact a portion of the sample. 
         [0053]    The plurality of support members may be arranged substantially parallel to one another. 
         [0054]    The support members may be of substantially square or rectangular cross-section. 
         [0055]    The basal portion may have a hollow, cupped body portion. 
         [0056]    Preferably the basal portion is arranged to receive a sample therein. 
         [0057]    Preferably the sample support is provided in the basal portion. 
         [0058]    The portions may be arranged to couple to one another at least in part by means of a friction fit. 
         [0059]    Preferably the complementary formations are formed from a material having a self-adhesive property. 
         [0060]    Preferably respective complementary formations are arranged to form a bond with one another. 
         [0061]    The bond may be a releasable bond. 
         [0062]    Alternatively the bond may be a substantially permanent bond. 
         [0063]    Preferably the complementary formations of a portion and a remainder of the portion are formed from substantially the same material. 
         [0064]    Preferably the one or more respective complementary formations of a portion are integrally formed with the portion. 
         [0065]    The complementary formations may be formed from a silicone material. 
         [0066]    Preferably at least one portion comprises a substantially transparent or translucent material thereby to allow light to irradiate a sample provided within the chamber. 
         [0067]    In a second aspect of the invention there is provided a bioreactor chamber assembly comprising:
       a chamber comprising a plurality of modules arranged to be coupled together to form the chamber, the chamber being arranged whereby one or more barriers may be provided within the chamber thereby to define a plurality of fluid reservoirs, at least one module of the chamber having a fluid inlet aperture and a fluid outlet aperture arranged whereby fluid flow through a reservoir may be established,   wherein respective modules are provided with one or more respective complementary formations arranged whereby the modules may be coupled to one another, the complementary formations comprising a resiliently deformable material and arranged whereby a liquid-tight seal may be formed between the respective formations without a requirement for a separate seal element.       
 
         [0070]    This has the advantage that because a separate seal element (such as an ‘O’ ring or any other seal element) is not required, assembly of a module may be made in a more rapid and convenient manner. Furthermore, a component count of a chamber may be reduced thereby simplifying manufacture and assembly. 
         [0071]    In addition, a compatibility of a seal element with liquid or other fluid in a chamber does not need to be verified. Thus, a usefulness of the chamber may be enhanced. A possibility of contamination of a content of a chamber due to an influence of a seal element is thereby eliminated. 
         [0072]    It is noted that the modules may correspond to the portions of the first aspect of the invention. 
         [0073]    Each reservoir may be associated with a different respective module. 
         [0074]    Preferably the barrier is provided at a location substantially between a pair of adjacent modules. 
         [0075]    The assembly may be arranged wherein the barrier is provided in the form of a substantially flat sheet of material. 
         [0076]    Preferably the barrier is arranged to allow passage of a prescribed substance therethrough. 
         [0077]    Preferably the barrier is arranged to allow passage of a prescribed substance therethrough wherein the substance is selected from amongst a fluid; a chemical compound, moiety or element; an ion; and a biological material. 
         [0078]    The assembly may be arranged wherein the fluid inlet of the at least one module is arranged such that fluid entering a reservoir of the chamber through the inlet aperture flows in a direction substantially parallel to a plane of a barrier defining a boundary of the reservoir. 
         [0079]    Preferably the modules have substantially the same cross-sectional area as one another. 
         [0080]    Preferably the modules may be releasably coupled to one another. 
         [0081]    Preferably the one or more formations of a first module comprise a rim of an end of a wall of the first module, the rim having a recess formed in a radially inner circumferential portion of the rim whereby the remaining portion of the rim defines a substantially circumferential skirt portion. 
         [0082]    Preferably a corresponding one or more formations of a second module comprise a corresponding portion of a rim of an end of a wall of said second module, the wall having a recess formed in a radially outer circumferential portion whereby the remaining portion of the wall defines a skirt portion having a shape and size complementary to that of the skirt portion of the first module. 
         [0083]    The first and second modules may be arranged to allow a membrane to be coupled between them by entrapment of a portion of the membrane between respective adjacent rims of the first and second modules. 
         [0084]    Preferably the assembly is arranged whereby entrapment of a membrane may be effected when adjacent modules are coupled to one another. 
         [0085]    Preferably the fluid inlet aperture and fluid outlet aperture of the at least one module are provided at substantially opposite locations of the wall of the chamber. 
         [0086]    Preferably the chamber is substantially cylindrical in shape. 
         [0087]    Preferably each module is substantially cylindrical in shape, the modules being arranged in a substantially coaxial configuration. 
         [0088]    Preferably the inlet aperture and the outlet aperture are provided at diametrically opposite locations of each module. 
         [0089]    Preferably the assembly comprises a module not having a fluid inlet aperture or a fluid outlet aperture. 
         [0090]    Preferably the assembly is further provided with a sample support arranged to support a sample in the form of a membrane, the support being arranged to allow each of a pair of opposed major faces of the membrane to be exposed to fluid contained within the chamber. 
         [0091]    Preferably the sample support comprises at least one support member arranged to contact a portion of the sample. 
         [0092]    Preferably the at least one support member comprises a ridged element, the ridged element being elongate in a substantially lateral direction thereby to provide an elongate surface upon which a sample may be placed. 
         [0093]    Preferably the at least one support member comprises at least one post element. 
         [0094]    Preferably the at least one post element is provided with an upper surface arranged to contact a sample, the upper surface being one selected from amongst substantially flat, substantially curved and substantially domed. 
         [0095]    Preferably the at least one support member comprises an element substantially in the form of a hemisphere or portion thereof. 
         [0096]    Preferably the sample support comprises a plurality of support members each support member being arranged to contact a portion of the sample. 
         [0097]    Preferably the plurality of support members are substantially parallel to one another. 
         [0098]    The support members may be of substantially square or rectangular cross-section. 
         [0099]    Preferably a cap module is provided comprising a module arranged to define a closed end of the chamber. 
         [0100]    Preferably the cap module has a hollow, cupped body portion. 
         [0101]    The cap module may be arranged to receive a sample therein. 
         [0102]    Preferably the sample support is provided in the cap module. 
         [0103]    A further cap module may be provided at an opposite end of the chamber to said cap module. 
         [0104]    Preferably the modules are arranged to couple to one another at least in part by means of a friction fit. 
         [0105]    Preferably the complementary formations are formed from a material having a self-adhesive property. 
         [0106]    Respective complementary formations may be arranged to form a bond with one another. 
         [0107]    The bond may be a releasable bond. 
         [0108]    Alternatively the bond may be a substantially permanent bond. 
         [0109]    The complementary formations and a remainder of the modules may be formed from substantially the same material. 
         [0110]    Preferably the one or more respective complementary formations of a module are integrally formed with the module. 
         [0111]    The complementary formations may be formed from a silicone material. 
         [0112]    Preferably at least one module comprises a substantially transparent or translucent material thereby to allow light to irradiate a sample provided within the chamber. 
         [0113]    In a third aspect of the invention there is provided bioreactor apparatus comprising a plurality of bioreactor chamber assemblies according to the second aspect wherein a first reservoir of a first chamber assembly is coupled to a first reservoir of a second chamber assembly. 
         [0114]    The first reservoirs of the first and second chambers may be coupled in series whereby fluid may be caused to flow through the first reservoir of the first chamber and subsequently through the first reservoir of the second chamber. 
         [0115]    Alternatively the first reservoirs of the first and second chambers may be coupled in parallel. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0116]    Embodiments of the invention will now be described with reference to the accompanying figures in which: 
           [0117]      FIG. 1  is a cross-sectional view of a chamber suitable for use in dual-cavity (or ‘dual-reservoir’) perfusion experiments; 
           [0118]      FIG. 2  is a cross-sectional view of rim portions of adjacent modules of the chamber of  FIG. 1  showing complementary formations by means of which the modules may be coupled together; 
           [0119]      FIG. 3  is a cross-sectional view of a configuration of a coupling between a basal portion of the chamber and a body module; 
           [0120]      FIG. 4  is a perspective view of a basal portion also showing a lower clamping plate; 
           [0121]      FIG. 5  is a cross-sectional view of rim portions of adjacent modules showing how a membrane may be gripped between adjacent modules; 
           [0122]      FIG. 6  is a cross-sectional view of a chamber suitable for use in triple-cavity perfusion experiments; 
           [0123]      FIG. 7  is a cross-sectional view of a chamber according to a further embodiment of the invention; 
           [0124]      FIG. 8  shows a chamber according to an embodiment of the invention; and 
           [0125]      FIG. 9(   a ) to ( c ) show assemblies of chambers according to embodiments of the invention; 
           [0126]      FIG. 10  shows a chamber assembly according to an embodiment of the invention in which a chamber is sandwiched between two clamp members in (a) perspective view and (b) cross-sectional view; 
           [0127]      FIG. 11  shows (a) an outer surface and (b) an inner surface of a clamp member according to an embodiment of the invention; 
           [0128]      FIG. 12  is a perspective view of a substrate having a pair of clamp members fixedly coupled thereto to which respective chambers may be attached; 
           [0129]      FIG. 13  is a plan view of the embodiment of  FIG. 12 ; and 
           [0130]      FIG. 14  shows an embodiment having a body portion and a basal portion clamped between clamp members. 
       
    
    
     DETAILED DESCRIPTION 
       [0131]      FIG. 1  shows a chamber  100  for a bioreactor according to an embodiment of the invention. The chamber  100  has a body portion  110  having a cap module  140  and a body module  150 . The cap module  140  and body module  150  are each provided with an inlet aperture  142 ,  152  and an outlet aperture  144 ,  154  respectively. 
         [0132]    The cap and body modules  140 ,  150  are arranged to couple together whereby a fluid-tight seal is formed between the modules. 
         [0133]      FIG. 2  shows a configuration of the structure of the coupling between the cap and body modules  140 ,  150 . It can be seen that rims  180 ,  185  of the cap and body modules  140 ,  150  respectively are provided with complementary formations. Thus, a rim  180  of the cap module  140  is provided with a recessed portion  181  along a radially inner circumferential edge of the rim  180  whilst a rim  185  of the body module  150  is provided with a recessed portion  186  along a radially outer circumferential edge. Skirt portions defied by respective remaining portions of rims  180 ,  185  are of a shape complementary to one another allowing coupling of the chambers together. 
         [0134]    In some embodiments the complementary formations are arranged to provide a friction fit. 
         [0135]      FIG. 3  shows a configuration of the structure of the coupling between the body module  150  of the chamber  100  and a basal portion  130 . It can be seen that similar formations are provided to those allowing the cap and body modules  140 ,  150  to be coupled together. In other words, a rim  118  of the body module  150  is provided with a recess  117  of a shape corresponding to that of a recess  138  formed in a rim  137  of the basal portion  130 . 
         [0136]    In some embodiments the basal portion  130  is formed from the same type of material as the cap and body modules  140 ,  150 . Thus in some embodiments the basal portion  130  is formed from a silicone rubber. Other materials are also useful. 
         [0137]      FIG. 4  shows a perspective view of a basal portion  130  formed from silicone rubber. The basal portion  130  is shown mounted on a clamping plate  190 . A corresponding clamping plate (not shown) is also provided that is arranged to be placed in abutment with the cap module  140  of the chamber  100 . The two clamping plates are then clamped together in order to enhance a fluid-tightness of a seal between the modules. Clamping also enables the chamber  100  to withstand greater internal pressure without suffering undue deformation. 
         [0138]    As illustrated in  FIG. 5 , the chamber  100  is configured to allow a first sample  101  in the form of a membrane  101  to be supported between the cap and body modules  140 ,  150  whereby a barrier to fluid flow between the cap and body modules  140 ,  150  may be formed. The membrane may be arranged to provide a molecularly selective filter. The membrane may allow diffusion or perfusion of molecules or other entities therethrough, including fluids or any required material. The membrane may in addition or instead provide a support for cells or other matter. 
         [0139]    In the arrangement of  FIG. 5  the membrane  101  is supported by being trapped between rims  180 ,  185  of the cap and body modules  140 ,  150  when the cap and body modules  140 ,  150  respectively are coupled together. Other methods of supporting the membrane  101  between the cap and body modules  140 ,  150  are also useful. 
         [0140]    It will be understood that clamping of modules together using a clamping plate  190  or other mechanism can beneficially increase a force trapping the sample  101  between rims  180 ,  185 . 
         [0141]    In some embodiments of the invention the body portion  110  and the basal portion  130  are formed from a resiliently flexible material such as a polymeric material. In some embodiments the portions  130 ,  110  are formed from a silicone material. In some embodiments the portions  130 ,  110  are formed from a transparent material whereby a sample within the chamber  100  may be subjected to irradiation with visible, infra-red and/or ultraviolet light through one or both of the portions  130 ,  110 . 
         [0142]    As can be seen in  FIG. 4  the basal portion  130  of the chamber  100  has a sample support portion  134  having a plurality of spaced apart ridge elements  136 . The ridge elements  136  are arranged to support a second sample  102  in such a manner that fluid within an internal cavity (or ‘reservoir’)  156  of the body module  150  of the chamber  100  is able to contact the second sample  102  on a face of the sample  102  that is towards the sample support portion  134  as well as an opposite face of the sample. 
         [0143]    This feature reduces a risk that a tissue sample will experience necrosis on the face that is towards the sample support portion  134 . Furthermore, this feature also facilitates removal of a sample  102  placed on the support portion  134 . If the sample  102  is placed in contact with a substantially flat surface the effects of surface tension can render the task of removing the sample  102  from the support portion  134  difficult. In such situations, samples such as thin membranes or glass cover-slips can otherwise become damaged during a process of removal. 
         [0144]    It is to be understood that other means for supporting a sample may be provided, such as a plurality of polygonal protrusions such as triangular, square or rectangular protrusions, or circular, spherical protrusions or protrusions of any other suitable shape. 
         [0145]    Whilst the embodiment of  FIG. 4(   a ) is provided with ridge elements, it is to be understood that in some other embodiments one or more post elements may be provided.  FIG. 4(   b ) shows an embodiment in which post elements are provided in the form of rectangular cuboids  137  whilst  FIG. 4(   c ) shows an embodiment in which post elements are provided in the form of domed elements  138 . Other shapes are also useful. In some embodiments one or more domed formations may be provided. 
         [0146]    The chamber  100  is arranged to allow two separate fluid flowpaths to be established therethrough when a barrier such as a sample  101  in the form of a membrane is provided between the cap and body modules  140 ,  150 . A first flowpath is arranged from the inlet aperture  142  to the outlet aperture  144  of the cap module  140 . A second flowpath is arranged from the inlet aperture  152  to the outlet aperture  154  of the body module  150 . 
         [0147]    In some embodiments, a flow of fluid or other substances between the cap and body modules  140 ,  150  is constrained to occur by transport through the sample  101 . 
         [0148]    It is to be understood that locations and sizes of the inlet aperture  142  and outlet aperture  144  of the cap module  140  and/or the locations of the inlet aperture  152  and outlet aperture  154  of the body module in the embodiment of  FIG. 1  may be arranged so as to minimise or at least reduce a deleterious effect of the fluid flow on samples  101  and/or  102 , respectively. 
         [0149]    For example, in some embodiments cell seeding or other phenomena may be arranged to occur on the second sample  102 , the first sample  101  being a membrane arranged to allow perfusion of fluid and/or certain molecules or other entities therethrough. Limiting a deleterious effect of the flow of fluid through the body module  150  on the growth, function and/or viability of cellular or other material on the second sample  102  may be an important factor in establishing suitable conditions. 
         [0150]    In some embodiments the outlet aperture of a module is arranged to be of a larger diameter than the inlet aperture of the module. In some embodiments the outlet aperture is greater than the inlet aperture by a factor of around 1.5 or more. In some embodiments the outlet aperture is greater than the inlet aperture by a factor of around 2 or more. 
         [0151]    The present inventors have determined that the height H in  of the inlet aperture  152  above the support portion  134  and the height H out  of the outlet aperture  154  above the support portion  134  ( FIG. 1 ) are factors that influence the fluid flow conditions at the support portion  134 . 
         [0152]    The inventors have recognised that heights H in  and H out  may be arranged to provide an optimum balance between larger values of H in  and H out  in order to achieve a reduced amount of shear stress on an upper surface of the second sample  102 , and smaller values of H in  and H out  in order to avoid an excessive amount of turbulent flow at the sample surface. The heights of the inlet and outlet apertures  142 ,  144  of the cap module  140  above the first sample  101  may also be selected so as to provide a balance between an amount of shear stress imposed on the sample  101  by flow of fluid through the cap module  140  and an extent to which flow of fluid through the cap module  140  occurs under laminar flow conditions. The heights may also be arranged to reduce or prevent depletion of oxygen or nutrients at the sample. 
         [0153]      FIG. 6  shows an embodiment of the invention in which a chamber  200  similar to that of  FIG. 1  is provided, the chamber  200  having a cap module  210  that is substantially the same as that of the chamber  100  of  FIG. 1  and first and second body modules  250 ,  260  each substantially identical to the body module  150  of the embodiment of  FIG. 1 . 
         [0154]    In the embodiment of  FIG. 6  the first and second body modules  250 ,  260  are stacked on top of one another such that the body portion  210  has first, second and third internal cavities  216 ,  256 ,  266 . 
         [0155]    The first and second internal cavities  216 ,  256  are arranged to be separated from one another by means of a first sample  201  whilst the second and third internal cavities  256 ,  266  are arranged to be separated from one another by means of a second sample  202 . A third sample  203  may be provided on a support portion  234  provided by the basal portion  230 . 
         [0156]    In some embodiments the first and second samples  201 ,  202  are membranes arranged to allow diffusion of required substances therethrough whilst the third sample  203  is a sample upon which cellular seeding is arranged to occur. 
         [0157]    A flow of fluid may be established independently through each of the first, second and third internal cavities  216 ,  256 ,  266  respectively. Respective inlet and outlet apertures  212 ,  214  (first cavity),  252 ,  254  (second cavity) and  262 ,  264  (third cavity) are provided to facilitate the flow of fluid through the respective cavities. 
         [0158]    For the reasons discussed above in relation to the embodiment of  FIG. 1 , the heights H in  and H out  of inlet aperture  262  and outlet aperture  264  of the third cavity  266  may be arranged to provide an optimum balance between an amount of shear stress imposed on an upper surface of the third sample  203  and an extent to which flow of fluid over the third sample  203  is turbulent. The heights may also be arranged to reduce or prevent depletion of oxygen or nutrients at the sample. 
         [0159]    Similarly, the heights of the inlet and outlet apertures of the cap module  210  and first body module  250  above first and second samples  201 ,  202  may also be adjusted to provide an optimum balance between the amount of shear stress imposed on the samples  201 ,  202  due to fluid flow through the modules  210 ,  250  and an extent to which flow of fluid at the surface of the samples  201 ,  202  is turbulent. The heights may also be arranged to reduce or prevent depletion of oxygen or nutrients at the sample. 
         [0160]    It is to be understood that due to the modular nature of the chamber  200 , a chamber  200  with substantially any number of body modules  250 ,  260  may be provided as required for any given application. In some embodiments body modules  250 ,  260  are substantially identical components. 
         [0161]      FIG. 7  shows an embodiment of the invention in which a basal module  370  is provided instead of a basal portion  130  ( FIG. 1 ). In the embodiment of  FIG. 7  the basal module  370  may be considered to be a combination of a body module  150  and a basal portion  130  of the embodiment of  FIG. 1 , the basal module  330  being provided in the form of a single module  370 . A basal module  370  according to the embodiment of  FIG. 7  has the advantage that a risk of fluid leaks from a seal formed between a body module  150  and a basal portion  130  of the embodiment of  FIG. 1  is reduced. 
         [0162]    It is to be understood that in some variations of the embodiment of  FIG. 7  one or more body modules  150  may be coupled between the cap module  310  and basal module  370  of the embodiment of  FIG. 7 . 
         [0163]      FIG. 8  shows a chamber  400  in which a cap module  411  and a basal module  471  are provided not having inlet apertures or outlet apertures. The cap module  411  is coupled to a body module  450  which is in turn coupled to the basal module  471  such that the body module  450  is sandwiched between the cap and basal modules  411 ,  471 . The body module  450  is provided with inlet and outlet apertures  452 ,  454  arranged to allow passage of fluid through the module  450 . 
         [0164]    A membrane  401  provides a barrier between an internal cavity  416  of the cap module  411  and an internal cavity  456  of the body module  450 . A membrane  402  provides a barrier between the internal cavity  456  of the body module  450  and an internal cavity  476  of the basal module  471 . 
         [0165]    In the embodiment of  FIG. 8  a supply of fluid may be provided in the internal cavities  416 ,  476  of the cap and basal modules  411 ,  471 . A chamber  400  according to the embodiment of  FIG. 8  can allow simulation of biological tissue that is fed by surrounding capillaries. Thus, for example tissue samples may be provided in one or both of the cap and basal modules  411 ,  471  and a supply of fluid passed through the body module  450 , the fluid passing through the body module  450  being arranged to simulate a flow of blood through capillaries associated with the biological tissue. The biological tissue may be provided on a sample support of one or both of the cap and basal modules  411 ,  471 . Alternatively or in addition the biological tissue may be provided on one or both of the membranes  401 ,  402 , for example on a side facing into the cavity of a respective cap or basal module  411 ,  471 . 
         [0166]      FIG. 9(   a ) shows an embodiment in which chambers  500  according to embodiments of the invention are coupled together in series to form an assembly of chambers. A corresponding assembly of chambers  500  coupled in parallel is shown in  FIG. 9(   b ). 
         [0167]      FIG. 9(   c ) shows an assembly of chambers in which a first chamber  600 A has a basal module  671  having no inlet or outlet aperture, the basal module  671  being coupled to a cap module  610  having an inlet aperture and an outlet aperture  612 ,  614 . A membrane  601 A is provided between the cap module and the basal module of the first chamber  600 A. 
         [0168]    The cap module of the first chamber  600 A is coupled to a cap module  610  of a second chamber  600 B, the cap module of the second chamber  600 B being similar to that of the first chamber  600 A in that it is also provided with an inlet aperture  612  and an outlet aperture  614 . 
         [0169]    The cap module  610  of the second chamber  600 B is coupled to a basal module  670  of the second chamber also having an inlet aperture  672  and an outlet aperture  674 . A sample  601 B in the form of a membrane is provided between the cap module  610  and the basal module  670 . A further sample may be provided on a sample support of the basal module  670  of the second chamber, the basal module  671  of the first chamber, or any other module of the first or second chambers  600 A,  600 B. 
         [0170]    It is to be understood that by suitable choice of chamber configuration by assembly of modules of different respective types a bioreactor may be formed suitable for the simulation of highly complex biological processes. 
         [0171]    Embodiments of the present invention provide a highly effective way of providing such bioreactors, allowing a user a very high degree of flexibility in choice of reactor configuration and an ability to make modifications and adjustments in a rapid and efficient manner. 
         [0172]    In the embodiment shown in the figures the cap, body and basal modules and the basal portion are arranged to couple to one another at least in part by means of a friction fit, allowing releasable coupling to one another in a convenient manner not requiring special tools. The modules and portion are formed from a silicone rubber material, being a resiliently deformable material having a self-adhesive property. This promotes the formation of a substantially water-tight joint between modules and/or between a module and the basal portion. 
         [0173]    In the embodiment shown the silicone rubber is formed to be substantially transparent to light, allowing exposure of cells within a chamber  100 ,  200 ,  300  to be exposed to light to test an influence of visible (or infra-red) light on cell function. 
         [0174]    It is to be understood that other materials and forms of material are also useful for forming the modules and basal portion. 
         [0175]    It will be apparent to persons skilled in the art that one or more modules and the basal portion may be formed by moulding. Other methods of forming the modules and basal portion are also useful. 
         [0176]      FIG. 10(   a ) shows an embodiment of the invention having a pair of clamp members  738 ,  748  arranged to sandwich a basal portion  730  and a body portion  710  of a chamber  700  therebetween. The embodiment of  FIG. 10(   a ) shows two chambers  700  so arranged. It is to be understood that in some embodiments only one chamber  700  is provided. The embodiment of  FIG. 10(   a ) also shows the two chambers  700  in a configuration in which one clamp member  738  is provided on a substrate  760 . In some embodiments the clamp member  738  is coupled to the substrate  760 . In some embodiments no substrate  760  is provided. 
         [0177]      FIG. 10(   b ) is a cross-sectional view of one of the chambers  700  shown in the embodiment of  FIG. 10(   a ). 
         [0178]    In some embodiments the clamp members  738 ,  748  are substantially identical. As can be seen from  FIG. 10  and  FIG. 11  the clamp members  738 ,  748  are in the form of disc-like members each having a side having a recessed well portion  739   a  and a corresponding rim portion  739   b  ( FIG. 11(   b )). The well portion  739   a  of one clamp member  738  is sized to receive a portion of the basal portion  730  of the chamber therein. 
         [0179]    The other clamp member  748  has a corresponding recessed well portion arranged to receive a portion of the body portion  710  therein. 
         [0180]    Thus in some embodiments the chamber  700  is arranged to be locatable between the clamp members  738 ,  748  whereby lateral movement of the clamp members with respect to the chamber  700  is constrained by the presence of the rim portions  739   b.    
         [0181]    In order to provide a clamping force between the clamp members  738 ,  748 , in the embodiment of  FIGS. 10 to 13  a pair of resilient elements are provided in the form of endless loops  751 ,  752 . The clamp members  738 ,  748  are provided with recessed channels  738   c  on an outer major surface thereof (being the surface opposite the surface in which the well portion  739   a  is provided). In the embodiment shown the recessed channels  738   c  are substantially parallel to one another and are provided at locations disposed equal distances D′ from a longitudinal axis L of the disc element  738 ,  748  but on opposite sides of the axis L. Thus, distance D′ is a radial distance of the closest point of channel  738   c  to the axis L. In some embodiments where the clamp member  738  is a disc-like member distance D′ is around two thirds of a radius of the clamp member  738 . Other distances are also useful. 
         [0182]    In the embodiment of  FIGS. 12 and 13  a lower clamp member  738  is coupled to a substrate  760  trapping the loops  751 ,  752  to lie within their respective channel  738   c.  The lower clamp member  738  may be coupled to the substrate  760  by permanent fixing means such as an adhesive or by means of releasable fixing means. The releasable fixing means may be a mechanical fixing element such as a screw or bolt, hook and loop fixing means (e.g. Velcro(R)), a releasable adhesive or any other suitable releasable fixing means. 
         [0183]    It can be seen from  FIG. 12  that a clamp member  748  (an upper clamp member) is positioned over the chamber with channels  748   c  of the upper clamp member  748  substantially parallel to those of the lower clamp member  738 . The endless loops  751 ,  752  are sized such that they can be positioned so as to lie in respective channels  748   c  of the upper clamp member  748 . The endless loops are arranged to exert a sufficient force to clamp the body portion  710  and basal portion  730  of the chamber  700  together to prevent leakage of fluid from the chamber through a joint between the body and basal portions  710 ,  730 . 
         [0184]    Embodiments such as that of  FIGS. 10 to 13  have the advantage that a substantially equal clamping force may be applied by respective resilient elements  751 ,  752  at substantially equal distances either side of the longitudinal axis L of the chamber  700 . Thus, clamping forces applied to the chamber  700  are balanced and a stable clamping arrangement may be provided. 
         [0185]    It is to be understood that this has the effect that a torque applied to a clamping member  738 ,  748  by one resilient element  751 ,  752  is arranged to act in an opposite direction and to be of substantially equal magnitude to a torque applied by the other resilient element  751 ,  752 . Thus a twisting force on the respective clamp members  738 ,  748  is substantially zero. This has the advantage discussed above that a stability of the assembly is enhanced. 
         [0186]    Furthermore a chamber  700  clamped between clamp members  738 ,  748  is subject to substantially uniform pressure by the clamp members  738 ,  748 . This has the advantage that a seal between the body portion  710  and basal portion  730  is also subject to uniform pressure by the clamp members  738 ,  748  reducing a risk of leakage of fluid. 
         [0187]    In some embodiments, resilient elements other than endless loops are provided. In some embodiments the resilient elements are in the form of resiliently extensible linear elements. The linear elements may be flexible elements, such as lengths of an elastomer. The linear elements may be provided with one or more hook elements to facilitate coupling of the linear elements to a clamp member. 
         [0188]    It is to be understood that in some embodiments the lower and upper clamp members  738 ,  748  may be formed integrally with basal and body portions of the chamber. Alternatively the lower and upper clamp members  738 ,  748  may be permanently coupled to basal and body portions of the chamber. In some embodiments the lower and upper clamp members  738 ,  748  are releasably coupled to basal and body portions of the chamber. 
         [0189]    Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of the words, for example “comprising” and “comprises”, means “including but not limited to”, and is not intended to (and does not) exclude other moieties, additives, components, integers or steps. 
         [0190]    Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise. 
         [0191]    Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.