Abstract:
A device for implanting in the body. The device comprises a chamber containing cells. The device also comprises an oxygen generator for providing oxygen to the cells.

Description:
FIELD OF THE INVENTION  
         [0001]    The present invention is in the field of devices implantable in a body, and more specifically to implanted devices containing living cells.  
         BACKGROUND OF THE INVENTION  
         [0002]    Several disorders arising from hyposecretion of one or more substances such as hormones are known. Among these are diabetes, Parkinson&#39;s disease, Alzheimer&#39;s disease, hypo- and hyper-tension, hypothyroidism, and various liver disorders. The hormone insulin, for example, is produced by β-cells in the islets of Langerhans of the pancreas. In normal individuals, insulin release is regulated so as to maintain blood glucose levels in the range of about 70 to 110 milligrams per deciliter. In diabetics, insulin is either not produced at all (Type 1 diabetes), or the body cells do not properly respond to the insulin that is produced (Type 2 diabetes). The result is elevated glucose levels in the blood.  
           [0003]    Disorders arising from hyposecretion of a hormone are usually treated by administration of the missing hormone. However, despite advances in understanding and treating many of these diseases, it is often not possible to precisely regulate metabolism with exogenous hormones. A diabetic, for example, is required to make several daily measurements of blood insulin and glucose levels and then inject an appropriate amount of insulin to bring the insulin and glucose levels to within the acceptable range.  
           [0004]    Organ transplantation is not a viable treatment today for most of these disorders for several reasons including rejection of a transplanted organ by the immune system. Isolated cells may be implanted in the body after being treated to prevent rejection. e.g. by immunosuppression, radiation or encapsulation. Methods of immunoprotection of biological materials by encapsulation are disclosed in U.S. Pat. Nos. 4,352,883, 5,427,935, 5,879,709, 5,902,745, and 5,912,005. The encapsulating material is selected so as to be biocompatible and to allow diffusion of small molecules between the cells of the environment while shielding the cells from immunoglobulins and cells of the immune system. Encapsulated β-cells, for example, can be injected into a vein (in which case they will eventually become lodged in the liver) or embedded under the skin, in the abdominal cavity, or in other locations. Fibrotic overgrowth around the implanted cells, however, gradually impairs substance exchange between the cells and their environment. Hypoxygenation of the cells ultimately leads to cell death.  
           [0005]    U.S. Pat. No. 5,855,613 discloses embedding cells in a thin sheet of alginate gel that is then implanted in a body.  
           [0006]    U.S. Pat. No. 5,834,005 discloses immunoisolating cells by placing them in a chamber that is implanted inside the body. In the chamber, the cells are shielded from the immune system by means of a membrane permeable to small molecules such as glucose, oxygen, and the hormone secreted by the cells, but impermeable to cells and antibodies. These implanted chambers, however, do not have a sufficiently high surface area to volume ratio for adequate exchange between the cells and the blood. Thus, also in this case, hypoxygenation ultimately leads to cell death.  
         SUMMARY OF THE INVENTION  
         [0007]    The present invention provides an implentable device comprising a chamber for holding functional cells and an oxygen generator for providing oxygen to the cells within the chamber. The cells, referred to herein as “functional cells”, are loaded into the chamber of the device that is then implanted in the body. The device comprises an oxygen generator. i.e. an element that can produce oxygen and make it available to the cells, so that the functional cells do not suffer from hypoxygenation. The oxygen generator thus produces oxygen and typically releases the oxygen in the cell&#39;s vicinity.  
           [0008]    The chamber has walls, which are permeable to nutrients needed by the cells as well as substances produced or secreted by the cells, such substances including, for example, metabolites, waste products produced by the cells and substances needed by the individual produced by the functional cells. In the body, the functional cells are immunoisolated from body constituents by the chamber&#39;s walls while being continuously exposed to adequate concentrations of oxygen, nutrients and hormones which penetrate the chamber&#39;s walls. The fact that oxygen is supplied to the cells by the oxygen generator allows the functional cells to maintain a high metabolic rate, so that a smaller number of functional cells are required for a given effect, as compared to prior art devices. The device containing the functional cells may be implanted in various parts of the body such as under the skin or in the peritoneum. The device may have any shape as required by a particular application. In accordance with one embodiment of the invention, the device is configured as a thin tubular element containing the functional cell within the tube&#39;s lumen. The device is typically of a size such that it may be implanted by injection through an introducer such as a syringe. Such an implantation procedure may be short and last only about 10 minutes. Other shapes of the device, e.g. a wafer shape, are also contemplated within the scope of the invention.  
           [0009]    In one embodiment, the oxygen generator comprises photosynthetic cells that convert carbon dioxide to oxygen when illuminated. The photosynthetic cells are preferably unicellular algae, for example, a high temperature strain of  Chlorella pyrenoidosa  (cat. No. 1230. UTEX) having an optimal temperature about equal to body temperature. Other photosynthetic cells that may be used with the invention include  Chlorella vulgaris, Scenedesmus obligus , Euglena, Volvox, and Spirolina. The photosynthetic cells may be autotrophic or mixotropic. Isolated chloroplasts may be used instead of, or in addition to, intact cells. In the case where the oxygen generator are photosynthetic cells the chamber comprises a light source, with an associated power source, such as a battery. The photosynthetic cells or chloroplasts may be contained within a separate compartment within the device, e.g. in the case of a device in the form of a tube, they may be contained within a thin elongated chamber contained within the tube (in essence a smaller diameter tube); or may be dispersed.  
           [0010]    In another embodiment, the oxygen generator comprises a pair of electrodes. When an electric potential is applied across the electrodes, oxygen is released by electrolysis of ambient water molecules present within the chamber. The electrodes are connected to a power source, typically a rechargeable battery.  
           [0011]    The chamber may further comprise an oxygen sensor that determines the oxygen concentration in the vicinity of the functional cells. A microprocessor may be provided to turn the oxygen generator when the sensor detects that the oxygen concentration is below a predetermined minimum and turns it off when the oxygen concentration is above a predetermined maximum.  
           [0012]    The functional cells pancreatic islet cells (α-cells. β-cells, etc.), hepatic cells, neural cells, renal cortex cells, vascular endothelial cells, thyroid cells, parathyroid cells, adrenal cells, adrenal cells, thymic cells ovarian cells, and testicular cells. In accordance with one currently preferred embodiment the functional cells are pancreatic β-cells, which are insulin-releasing cells. Such a device may be configured for use in the treatment of insulin-dependent diabetes or for monitoring glucose levels in the body. As another example, the functional cells may be hepatic cells, whereby the device can serve as an “artificial liver”.  
           [0013]    The functional cell population in the device may be in the form of individual, may be in the form of cell clusters, or as pieces of excised tissue. These tissues or cells include, without limitation, tissue or cells removed from a donor animal, tissue or cells obtained by incubation or cultivation of donor tissues and cells, cells obtained from viable cell lines, cells obtained by genetic engineering. The cells may be of human or animal origin as well as genetically engineered or cloned cells or stem cells. The cells may be autologous or heterologous with the recipient&#39;s cells. The tissues or cells may perform a useful function by secreting a beneficial substance into the body, such as hormones or neurotransmitters, or removing a harmful substance from the body by taking them up, such as in the case of hepatic cells which may take up various toxic substances. The cells, cell clusters or tissue pieces may be dispersed in a liquid medium or matrix within the chamber or may be attached to a substrate, e.g. the walls of the chamber.  
           [0014]    In another application, the chamber of the present invention is used to implant cells in the body as part of a system for detecting or monitoring the level of a substance in body fluids. Such a system comprises an implentable device of the invention having a detector adapted to monitor a property of the functional cells that is correlated with the level of the substance in the medium surrounding the functional cells. For example. U.S. Pat. No. 5,101,814, discloses use of a chamber for implanting glucose sensitive cells into the body and monitoring an optical or electrical property of the cells that is correlated with glucose levels. The present invention may incorporate a detector arrangement of the kind disclosed in U.S. Pat. No. 5,101,814.  
           [0015]    The present invention further concerns a method for treating an individual suffering from a substance-deficiency by implanting in the individual a device of the invention containing functional cells, which can secrete said substance. For example, if the individual suffers from insulin-dependent (type I) the functional cells may be pancreatic β-cells.  
           [0016]    By another embodiment the method may employed for treating an individual suffering from a condition where a beneficial effect may be achieved by removal of a substance from the body, such as in cases of a liver mal-function. The functional cells, in accordance with this embodiment are capable of removal of such substance.  
           [0017]    The present invention further concerns a method of monitoring level of a substance in an individual&#39;s body, comprising implanting the above system in the individual&#39;s body and monitoring the reading of said detector.  
           [0018]    The power source in the device of the invention is typically a rechargeable battery. The device preferably comprises a recharging circuitry linked to said batter. For remote induction recharging of the battery as known per se. The device preferably comprises also an electronic circuitry for monitoring parameters of the device or its surrounding or for controlling operational parameters of the device. Such monitored parameters may be parameters influencing the functional cells&#39; viability or the level of production of a needed substance e.g. the oxygen level; the level of a produced needed substance; the level in body fluids of a substance which is to be produced or removed by the device; etc. The monitored parameters may, for example, be used in order to control the level of oxygen production (by controlling the current to the electrodes or the light generated by the light source, as the case may be). The control circuitry may comprises means for wireless communication with an external device, as known per se. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0019]    In order to understand the invention and to see how it may be carried out in practice, preferred embodiments will now be described, by way of non-limiting examples only, with reference to the accompanying drawings, in which:  
         [0020]    [0020]FIG. 1 is a device according to a first embodiment of the invention;  
         [0021]    [0021]FIG. 2 is a device according to a second embodiment of the invention;  
         [0022]    [0022]FIG. 3 is a device according to a third embodiment of the invention: and  
         [0023]    [0023]FIG. 4 is a device according to a fourth embodiment of the invention. 
     
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS  
       [0024]    First Embodiment  
         [0025]    Referring first to FIG. 1, an embodiment of the device of the invention, is shown in cross-sectional (FIG. 1 a ) and longitudinal (FIG. 1 b ) view. The device has a chamber  100  having the overall shape of a thin cylinder. The chamber thus has an extremely large surface area to volume ratio allowing both efficient exchange of nutrients and waste and simple insertion and retrieval into and out of the peritoneum, or any other body area. The chamber  100  is flexible and may be made to assume any desired configuration in the body.  
         [0026]    Outer membrane  105  is formed from a semipermeable material, for example, a polyvinyl chloride acrylic copolymer. The molecular weight cut-off of the outer membrane  105  is selected so that the outer membrane  105  is permeable to nutrients and active substances, such as hormones secreted by the cells but is impermeable to immunoglobulins and cells. The molecular weight cutoff of the outer membrane  105  is preferably between 10,000 and 70,000 Dalton. The outer membrane  105  has an anti-fibrin coating  145  that inhibits fibrotic overgrowth.  
         [0027]    Inner membrane  110  is permeable to small inorganic molecules such as gases water and salts. The molecular weight cutoff of the inner membrane  110  is preferably between 100 and 200 Dalton. The inner membrane  110  may be made from materials commonly used for artificial lung membranes for example, such materials as are disclosed in U.S. Pat. No. 5,614,378. The interior  130  of inner membrane  110  contains photosynthetic cells  135 . The photosynthetic organisms may be, for example, unicellular algae such as Chlorella. A light source  140  produces light preferably having a wavelength in the range of 400 to 700 nm. Light is guided from the light source  140  along the length of the chamber  100  by an optic fiber  148 . The chamber  100  contains a power source- 155 , a microprocessor  150  that may be for example, a rechargeable battery or any other kind of power source, and an oxygen sensor  160 . The photosynthetic cells  135  constitute an oxygen generator.  
         [0028]    Prior to implantation of the chamber  100  into the recipient&#39;s body, functional cells  120  are loaded into the annular space  115  between outer membrane  105  and inner membrane  110 . The functional cells  120  may be, for example, pancreatic islets, in which case about  10   6  islets are sufficient to produce adequate amounts of insulin to regulate glucose levels in the recipient&#39;s body. The functional cells  120  may be suspended in a liquid medium in the annular space  115  or immobilized in the annular space  115  by embedding in a gel matrix formed, for example, from alginate, polylysine, chitosan, polyvinyl alcohol, polyethylene glycol, agarose, gelatin, or k-carrageenan.  
         [0029]    After being loaded with the functional cells  120 , the chamber  100  is implanted into the body by means of an applicator that may be, for example, a syringe. The processor  150 , the light source  140  and the power source  155  may also be implanted in the body, or may in use be external to the body. If the light source  140  in use is external to the body, the optic fiber  148  is configured to pass through the skin. If the processor  150  in use is external to the body, the oxygen sensor  160  is configured to pass through the skin.  
         [0030]    When oxygen sensor  160  detects that the oxygen level in the annular space  115  is below a predetermined minimum, the light source  140  is turned oil by the microprocessor  150  in order to induce photosynthesis by the photosynthetic cells  135 . The oxygen produced by photosynthesis in photosynthetic cells  135  is released from the photosynthetic cells  135  and diffuses through the inner membrane  110  into the annular space  115  and is thus made available to the functional cells  120 . When oxygen sensor  160  detects that the oxygen level in the annular space  115  is above a predetermined maximum, the light source  140  is turned off by the microprocessor  150  in order to stop photosynthesis by photosynthetic cells  135 , so as to conserve the power source  155 . About 10 9 -10 10  Chlorella cells are sufficient to produce an adequate supply of oxygen for 10 6  functional islets.  
         [0031]    The power source  155  may periodically be recharged when the chamber  100  is inside the body. For example, electrical contacts (not shown) normally located outside the body may be connected via a percutaneous cable to the terminals of the power source  155 . An external voltage is then applied across the contacts so as to recharge the power source  155 . Alternatively, the power source  155  may be recharged inductively by applying an electric field externally on the skin in the vicinity of the chamber  100 .  
         [0032]    Second Embodiment  
         [0033]    Referring now to FIG. 2, a second embodiment of the invention, is shown in cross-sectional (FIG. 2 a ) and longitudinal (FIG. 2 b ) view. This embodiment is similar to the first embodiment shown in FIG. 1, and identical components are identified by the same numeral. A pair of flexible electrodes  315   a  and  315   b  extends along the length of the chamber  300  in the interior  130  of the inner membrane  110 . The electrodes are made of a biocompatible material such as carbon or platinum. The chamber  300  contains a power source  355 , a microprocessor  350 , and an oxygen sensor  160 . The electrodes  315   a  and  315   b  constitute an oxygen generator.  
         [0034]    Prior to insertion of the chamber  300  into the recipient&#39;s body, functional cells  120  are loaded into the annular space  115  between outer membrane  105  and inner membrane  110 . The functional cells may be suspended in a liquid medium in the annular space  115  or immobilized by embedding the functional cells  120  in a gel matrix formed, for example, from alginate, polylysine, chitosan, polyvinyl alcohol, polyethylene glycol, agarose, gelatin, or k-carrageenan.  
         [0035]    The chamber  300  is then implanted in the body using an applicator that may be, for example, a syringe. The processor  350  and the power source  355  may also be implanted in the body or may in use be external to the body. If the processor  350  in use is external to the body, the electrodes  315   a  and  315   b  and the oxygen sensor  160  are configured to pass through the skin.  
         [0036]    In the body, when oxygen sensor  160  detects that the oxygen level in the annular space  115  is below a predetermined minimum, the microprocessor  350  causes an electric potential to be generated between the electrodes  315   a  and  315   b  by means of the power source  355 . This causes hydrolysis of water molecules in the interior  130  of inner membrane  110 , producing oxygen. The oxygen molecules diffuse through inner membrane  110  into the annular space  115  between inner membrane  110  and outer membrane  105 , and is thus made available to the functional cells  120 . When the oxygen sensor  160  detects that the oxygen level in the annular space  115  is above a predetermined maximum, the electrical potential across the electrodes  315   a  and  315   b  is turned off by microprocessor  350 , so as to conserve the power source  155 . The power source  155  may be recharged when the chamber  300  is inside the body as described in reference to the previous embodiment.  
         [0037]    Third Embodiment  
         [0038]    In FIG. 3, another embodiment of the invention is shown. This embodiment has components in common with the embodiment of FIG. 1 and similar components are identified with the same numeral. This embodiment has a chamber  400  that is formed as a thin planar or wafer-like shape that is implanted in the body close to the skin  402 . The surface  405  of the chamber  400  closest to the skin  402  is transparent to light. The photosynthetic cells  135  and functional cells  120  are located in the interior  410  of the chamber  400 . The photosynthetic cells  135  are irradiated with light from a light source  415  located outside the body. Light from the light source  415  penetrates through the skin  402  and the surface  405  to the interior  410  of the chamber  400 . The processor  150  and the power source  155  may also be implanted in the body or may in use be located external to the body. The light source  415  may be integral with the device as shown in FIG. 3 a . In this case when the oxygen sensor  160  detects that the oxygen level in the interior  410  of the device  400  is below a predetermined minimum, the light source  415  is turned on by the processor  150  in order to induce photosynthesis of the photosynthetic cells  135 . When the oxygen server  160  detects that the oxygen level in the interior  410  is above a predetermined maximum, the light source  415  is turned off by the processor  150 .  
         [0039]    The photosynthetic cells may also be illuminated by a light source  415  that is independent of the processor  150  as shown in FIG. 3 b . In this case when the oxygen sensor  160  detects that the oxygen level in the interior  410  of the device  400  is below a predetermined minimum, the processor  150  generates a sensible signal such as an audible signal produced by a loudspeaker  450 . This indicates to the individual that he must irradiate the skin  402  overlying the chamber  400  in order to induce photosynthesis of the photosynthetic cells  135 . When the oxygen sensor  160  detects that the oxygen level in the interior  410  is above a predetermined maximum, the processor  450  discontinues the sensible signal, thus informing the individual that the illumination should be stopped.  
         [0040]    Fourth Embodiment  
         [0041]    In FIG. 4, yet another embodiment of the invention is shown. This embodiment has components in common with the embodiment of FIG. 3 and similar components are identified with the same numeral. This embodiment has a chamber  500  that is formed from a solid gel such as alginate, polylysine, chitosan, polyvinyl alcohol, polyethylene glycol, agarose, gelatin, or k-carrageenan. The gel is preferably transparent to light. The photosynthetic cells  135  and functional cells  120  are embedded in the gel. The photosynthetic cells  135  are irradiated with light from a light source  415  located outside the body. Light from the light source  415  penetrates through the skin  402  and the gel to the photosynthetic cells. The processor  150  and the power source  155  may also be implanted in the body or may in use be located external to the body. The light source  415  may be integral with the device as shown in FIG. 4 a . In this case when the oxygen sensor  160  detects that the oxygen level in the interior  510  of the device  400  is below a predetermined minimum, the light source  415  is turned on by the processor  150  in order to induce photosynthesis of the photosynthetic cells  135 . When the oxygen sensor  160  detects that the oxygen level in the interior  510  is above a predetermined maximum, the light source  415  is turned off by the processor  150 .  
         [0042]    The photosynthetic cells may also be illuminated by a light source  415  that is independent of the processor  150  as shown in FIG. 4 b . In this case when the oxygen sensor  160  detects that the oxygen level in the interior  510  of the chamber  500  is below a predetermined minimum, the processor  150  generates a sensible signal such as an audible signal produced by a loudspeaker  450 . This indicates to the individual that he must irradiate the skin  402  overlying the chamber  500  in order to induce photosynthesis of the photosynthetic cells  135 . When the oxygen sensor  160  detects that the oxygen level in the interior  410  is above a predetermined maximum, the processor  150  discontinues the sensible signal thus informing the individual that the illumination should be stopped.