Abstract:
A pouch for forming an implantable artificial organ, including a closed shell provided in a semi-pervious membrane. The pouch further includes a sheet contained within the shell, the sheet including projections on the surface thereof for maintaining a space for cells between the sheet and the shell.

Description:
PRIORITY CLAIM 
       [0001]    The present application is a National Phase entry of PCT Application No. PCT/FR2011/051607, filed Jul. 6, 2011, which claims priority from French Application No. 1056004, filed Jul. 22, 2010, the disclosures of which are hereby incorporated by reference herein in their entirety. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates to a pouch for forming an implantable artificial organ such as a pancreas. 
       BACKGROUND 
       [0003]    The first attempts to produce an implantable artificial organ in humans or animals took place a number of decades ago. The objective is to replace a missing organ with a device containing cells satisfying at least one function of said organ while avoiding the constraints of a transplant. 
         [0004]    Document FR 2 384 504 already proposes an artificial pancreas supplied with a body fluid to be treated. The fluid passes through a serpentine element housed in a chamber that contains pancreatic islets. The wall of the serpentine element is made of a material that enables exchanges of molecules of low molecular weight such as insulin and glucose, but that forms a barrier to larger molecules such as antibodies and antigens. However, such a device is not implantable. 
         [0005]    An implantable artificial organ was proposed by document WO 94/18906. Cells are contained in an envelope made of a semi-permeable membrane, which envelope is contained in another container providing mechanical protection of the first envelope. The cells are, for example, thyroid cells, parathyroid gland cells, adrenal gland cells, liver cells or pancreas cells. The replacement of the cells requires complete replacement of the device. 
         [0006]    Document EP 664 729 proposes an implantable and refillable artificial pancreas. 
         [0007]    Semi-permeable membranes have been the subject of numerous much research projects. Document WO 02/060409 proposes, for example, a semi-permeable membrane for encapsulating cells made of porous polycarbonate and surface-treated with a hydrophilic polymer. These membranes have the expected characteristics, namely good control of permeability, allowing the nutrients and substances generated by the cells of the artificial organ to quickly pass, limited adhesion of the cells on the surface of the membrane so as not to hinder the exchanges, good mechanical resistance and impermeability to large molecules. However, pouches made of this material do not control the distribution of the islets inside. Masses may form, which then have trouble exchanging nutrients and substances produced. 
         [0008]    Accordingly, there is a need for a pouch for forming an implantable artificial organ that ensures good distribution of active cells and that is resistant during and after implantation of the pouch. 
       SUMMARY OF THE INVENTION 
       [0009]    With these objectives in view, the present invention relates to a pouch for forming an implantable artificial organ comprising a closed envelope made of a semi-permeable membrane, characterized in that it comprises a sheet contained in the envelope, the sheet comprising, at its surface, protuberances so as to maintain a space for cells between the sheet and the envelope. 
         [0010]    The cells of the artificial organ can thus be housed between the protuberances over the entire surface of the sheet without being compressed by the envelope against the sheet. It is noted that the cells do not form masses and retain a large exchange surface, thereby guaranteeing their durability. 
         [0011]    The sheet comprises, for example, protuberances on both of its faces. 
         [0012]    According to a particular embodiment, the protuberances have the shape of dashes spaced apart from one another and forming regularly distributed lines parallel to one another. This arrangement defines channels in the direction in which the fluids may easily circulate, channels being oriented, for some, in the direction of the dashes, and, for others, obliquely with respect to said dashes. 
         [0013]    According to another embodiment, the pouch comprises at least one connector comprising a body attached to the sheet, and a conduit connected to the connector so as to be in hydraulic communication with the inside of the pouch. It is thus possible to fill or empty the pouch. The attachment of the connector to the sheet makes it possible for the envelope to be protected from stresses that may occur between the pouch and the conduit, because the stresses are taken up by the sheet. The sheet can be mechanically reinforced, while the envelope preserves its thinness necessary for ensuring its semi-permeability. 
         [0014]    In one embodiment, the pouch also comprises an implantable percutaneous chamber connected to the conduit so that the implantable percutaneous chamber is in hydraulic communication with the inside of the pouch. The implantable percutaneous chamber is a closed receptacle placed under the skin of a person or an animal and that can be accessed by a needle through the skin and a septum of the chamber. Thus, the contents of the pouch can be renewed usually without the skin being passed through by a conduit. 
         [0015]    In particular, the connector can comprise a base, the sheet being clamped between the base and the body in order to attach the connector to the sheet. The clamping makes it possible to obtain a mechanical connection that does not weaken the sheet at the junction. 
         [0016]    In one particular embodiment, pouch comprises at least two connectors, one of which comprises a grid inserted in the hydraulic passage. It is thus possible to establish circulation between the two connectors so as to ensure the renewal of the contents of the pouch. The presence of a grid makes it possible to retain the cells if they are to be kept in the pouch. For this, the connector with a grid is used for the suction. If the cells are to be renewed, circulation is established in the opposite direction so that the cells will be discharged by means of the connector without a grid. 
         [0017]    The connector can comprise a cap, an upper membrane of the envelope being clamped between the body and the cap so that the connector passes tightly through the upper membrane. Here as well, the clamping technique makes it possible to pass through the envelope without any risk of damage to it. 
         [0018]    The sheet is, for example, made of silicone. This material has good properties of flexibility, resistance to stretching, and receptiveness to cells to be contained in the pouch. 
         [0019]    In another embodiment, the silicone sheet has a surface treatment of the SI-HPMC-CMC type. SI refers to silicone, HPMC refers to hydroxypropyl-methylcellulose and CMC refers to carboxymethyl cellulose. This treatment makes it possible to increase the biocompatibility properties of the pouch. 
         [0020]    In another embodiment, the sheet comprises a textile reinforcement core. This core is, for example a polyester fabric. It makes it possible to control the possible elongation of the sheet under stress, in particular for stresses transmitted by the connectors. 
         [0021]    The envelope can be formed by two membranes heat-sealed together. The method for forming the envelope is simple and makes it possible to enclose the sheet in the envelope. The pouch may comprise a silicone frame covering the seam. The frame prevents or inhibits the heat-sealed edges from aggravating the tissue surrounding the pouch. 
         [0022]    In another embodiment, the pouch also comprises a permeable over-envelope surrounding the envelope. Thus protection of the envelope made of semi-permeable material is provided without limiting the exchanges between the tissues surrounding the pouch and the inside of it. This protection is particularly useful during the implantation phase in which the risks of tearing are high. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0023]      FIG. 1  is a perspective view of a pouch according to one embodiment of the invention; 
           [0024]      FIG. 2  is a perspective and exploded cross-section view of the pouch of  FIG. 1  at a connector; 
           [0025]      FIG. 3  is a partial perspective view of the pouch at a connector and representing the sheet and the base of a connector; 
           [0026]      FIG. 4  is a cross-section view of the connector of the pouch of  FIG. 1  in the assembled position. 
       
    
    
     DETAILED DESCRIPTION 
       [0027]    A pouch  1 , according to one embodiment of the invention shown in  FIGS. 1 to 4 , has a general planar rectangular shape. As shown in  FIG. 1 , the pouch  1  has two conduits  10  extending from two connectors  11  to two implantable percutaneous chambers  12 . 
         [0028]    The pouch  1  comprises an envelope  13  containing a sheet  14 . The envelope  13  is formed by two membranes  131 ,  132  made of thermoplastic material sealed together along their edges. The dimensions of the sheet  14  are adjusted so that the sheet is contained within the envelope  13  when flattened. The surface of the sheet  14  is, for example, 50 to 200 cm 2 . 
         [0029]    The sheet  14  is produced by molding a silicon-based elastomer material. It comprises a polyester textile core  140  that is over-molded. It comprises, on its two faces, protuberances  141  shaped as dashes spaced apart from one another and forming lines regularly distributed parallel to one another. Aside from the protuberances  141 , the sheet  14  has a thickness of between 0.2 to 0.6 mm. The dashes  141  have, for example, a length of 1 to 5 mm, and the lines are spaced apart by a distance of 1 to 2 mm. The interval between the dashes is, for example, 1 to 2 mm. Locally, the dashes  141  are reinforced by rings  142  having a diameter of around 1 mm. The height of the protuberances  141  is, for example 0.2 to 0.8 mm. The periphery of the sheet  14  comprises a bead  143  of the same height as the protuberances  141 . The surface of the sheet  14  is treated by a SI-HPMC-CMC coating, which reduces the surface tension of the sheet  14  in order to reduce the adhesion of the cells to the sheet  14  and reduce the secretion of proinflammatory mediators. 
         [0030]    The two membranes  131 ,  132  forming the envelope  13  are semi-permeable so as to enable the transfer of small molecules but stop the large molecules, such as, for example, polycarbonate membranes as described in document WO 02/060409. The two membranes  131 ,  132  are heat-sealed at their periphery to form the envelope  13 . 
         [0031]    A frame  130  made of silicon has a U-shaped cross-section and surrounds the periphery of the envelope  13  so as to cover the seam of the two membranes  131 ,  132 . 
         [0032]    Hydraulic communication is established between the implantable percutaneous chambers  12  by the two conduits  10  by passing through the inside of the envelope  13 . For this, each conduit  10  is connected to a connector  11 , which produces the passage between the inside and the outside of the envelope  13 . 
         [0033]    Each connector  11  comprises a cap  111 , a body  112  and a base  113 . One of the two connectors  11  also comprises a filtration grid  114 . The cap  111  comprises a central cavity  1110  connected to a sleeve  1111 , which receives the conduit  10 . The conduit  10  is, for example, bonded to the inside of the sleeve  1111 . The body  112  has an annular shape and comprises three body teats  1120  projecting toward the cap  111 . The cap  111  comprises three holes  1112  opposite the body teats  1120  so as to produce an assembly between the body  112  and the cap  111  by fitting the body teats  1120  into the holes  1112 . The body  112  also comprises an annular bulge  1121  corresponding to a recess  1113  of complementary shape produced in the cap  111 , so as to clamp and hold one of the membranes  131 , called an upper membrane, between the cap  111  and the body  112 . In this location, the upper membrane  131  is drilled so as to allow the body teats  1120  to pass through. The central opening  1122  of the body  112  is opposite the central cavity  1110  of the cap  111  so that hydraulic communication can be established between them. If a grid  114  is present, it is housed in a shoulder  1114  of the cap  111 , where the central cavity  1110  opens toward the body  112 . 
         [0034]    The base  113  also has a planar annular shape and comprises three base teats  1131  projecting toward the body  112  so as to be fitted into the corresponding holes  1123  of the body  112 . This makes it possible to clamp the sheet  14  between the base  113  and the body  112 . To do this, the sheet  14  comprises a cut  144  corresponding to the three base teats  1131  and to the central opening  1122  of the body  112 . The protuberances  141  are also interrupted so as to enable planar support of the clamping area between the body  112  and the base  113 , as shown by  FIG. 3 . The central opening  1132  of the base  113  is also opposite the central cavity  1110  of the cap  111  so as to establish hydraulic communication between them. 
         [0035]    The teats  1120 ,  1131  receive, for example, adhesive in order to produce the permanent assembly of parts  111 ,  112 ,  113  with one another. In another embodiment, the fitting may be forced or conical, or the teats may be welded by ultrasound. 
         [0036]    The components  111 ,  112 ,  113  of the connector  11  are produced by plastic polypropylene injection. They may receive a surface treatment so as to increase biocompatibility. 
         [0037]    The assembly of the pouch  1  is produced as follows. The base  113  of each connector  11  is placed under the sheet  14 . The body  112  of each connector  11  is placed above the sheet  14  and assembled with the corresponding base  113  by clamping the sheet  14 . The membranes  131 ,  132  are placed below and above the sheet  14 , then they are sealed together at the edges. The frame  130  is placed by bonding in order to cover these seams. The cap  111  of the connectors  11  is placed above the upper membrane  131  and assembled with the corresponding body  112  by clamping the upper membrane  131  between the recess  1113  and the bulge  1121 . As the case may be, the grid  114  is placed in the shoulder  1114  of the cap  111  before assembly with the body  112 . The conduits  10  are connected to the caps  111  and to the implantable percutaneous chambers  12 . 
         [0038]    During use of the pouch  1 , it is rolled up if necessary and inserted into a body through a small incision, then unrolled. The implantable percutaneous chambers  12  are also inserted and placed under the skin. When it is certain that the pouch  1  is well tolerated by the receiving body, the cells are introduced with a syringe by the implantable percutaneous chamber  12  connected to the connector  11  without a grid. The elements introduced pass into the implantable percutaneous chamber  12 , then into the conduit  10 , into the central cavity  1110  of the cap  111 , through the openings of the membrane and the body  112 , then through the cut  144  of the sheet  14 . The cells are distributed in the pouch  1  and are housed between the protuberances  141 . Optionally, fluid circulation is established by suction through the other implantable percutaneous chamber  12 . 
         [0039]    The invention is not limited to the example described above. The pouch may be disc-shaped or have any planar shape. The protuberances may be in the shape of pins, bosses, rings or cones. The connectors  11  may be made of biocompatible materials other than polysulfone or polycarbonate. A permeable over-envelope may surround the envelope. The frame  130  is not essential, in particular if an over-envelope is present.