JPS6112699B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to medical devices, and more particularly to artificial glands.

Many functions of an animal's body are controlled by biochemical substances called hormones. These substances are produced by organs in the body called glands and secreted into the body's circulatory system (both blood and lymph) for action at distant locations. Different glands secrete different hormones that control different functions of the body.

One of the well-known glands is the pancreas. Part of this gland secretes insulin into the bloodstream to control blood sugar levels. Insulin is produced in cells called B cells at locations within the pancreas called the islets of Langerhans. Glandular abnormalities of the pancreas are best evidenced by insufficient production of insulin. This increases blood sugar levels and, if unchecked, can lead to severe or fatal coma. The condition is known as diabetes.

Currently, diabetes is commonly controlled by injecting insulin into the body. This insulin diffuses into the bloodstream and regulates blood sugar levels. Insulin injections do not alleviate the underlying abnormality (pancreatic malfunction), but merely reduce the overall effects of the abnormality, ie, the rise in blood sugar. Attempts have been made to fundamentally correct pancreatic defects by transplanting healthy organs from one animal's body to another. Although this procedure has had some success, it almost always fails after a period of time due to either the body rejecting the transplant (normal rejection) or the body rejecting the transplanted organ (``transplant versus host'' rejection). Such rejection is caused by cell-mediated destructive host antibodies (generally 4 dia.
It is caused by a transplant antigen (a special chemical produced by a foreign body in a new biological environment) that stimulates a protein molecule larger than a micron in size.

A graft is prepared by enclosing the transplanted organ or organ cells in a container of inert plastic material having closed side and bottom walls and an open top wall lined with a porous membrane of cellulose. Attempts have been made to suppress host rejection by Membranes regulate the movement of substances between an organ or cell and its surrounding environment. The container is surgically implanted within the patient's body at a location exposed to body fluids. Although this method has had some success in suppressing the immune response,
Disadvantages include the need for surgical insertion of the organ or cell-loaded material and the need for periodic surgeries to renew and regenerate the implanted organ or cells. Moreover,
The effectiveness of this method is limited by the lack of sufficient fluid flow at the site of implantation of the container, as well as by the limited number of sites that can be implanted.

Therefore, one objective of the present invention is to obtain an artificial gland structure.

Another object of the invention is to obtain an artificial gland structure that can be easily used externally as well as internally in the body.

It is a further object of the present invention to provide an artificial gland structure that can be easily attached to the exterior of a patient's body and easily replaced if necessary.

A further object of the present invention is that the cells or glands placed in the container are continuously and thoroughly "washed" by the nourishing fluid, yet are able to prevent rejecting antibodies. The goal is to obtain an artificial gland structure.

Another object of the present invention is to maintain the cells or organs placed in the container continuously and to rapidly disseminate their special hormones according to the physiological needs of the body of the animal. The aim is to obtain an artificial glandular construct that is easily connected to the animal's bloodstream.

A further object of the present invention is to obtain an artificial glandular construct that can be easily used to correct glandular defects in endocrine glands.

Another object of the present invention is that the islet cells are not rejected and are easily used by diabetic patients to make the exact amount of insulin that is used by the body as required by menstruation at a given time. The aim is to obtain an artificial gland structure used for.

The artificial gland structure according to the invention is made of a fluid-tight shell having a fluid inlet and a fluid outlet connected in series to the blood flow within the body of an animal, and a membrane of pores completely enclosed within the shell. ing. The membrane separates blood flow from one or more cavities in the torso that house the cells of an organ. The membrane has many fine pores, and substances larger than a few microns, preferably larger than 1 micron, cannot pass through the membrane. The membrane thus restricts the movement of substances between the cells and the bloodstream, which "washes" the membrane as it passes through the structure.

Glucose and other cellular nutrients can easily pass through pores less than 1 micron in diameter from the bloodstream into the cavities that house the cells. Furthermore, in the case of islet cells taken from the pancreas, desirable cell products such as insulin, as well as certain waste products from the cells, can easily pass through the membrane from the cavity where the cells are placed into the bloodstream. be able to. However, unwanted substances such as antigens produced by cells in the cavity, or antibodies in the bloodstream, especially cell-mediated antibodies, cannot pass through the membrane's micron-sized pores. . Therefore, immune reactions (host vs. graft or graft vs. host) are prevented. The membrane thus filters out harmful products that reduce or destroy the effectiveness of mass transfer actions, but selectively allows essential cellular nutrients and cellular by-products to easily pass through the membrane walls as needed. It becomes a filter that can

Living cells (hereinafter cell is to be understood to include whole organs or parts of organs, as the case may be) are placed inside the torso structure before the structure is sealed in a fluid-tight manner. Alternatively, the structure may be made in some other manner, sealed, and then poured into the cavity of the shell. Typically, the cells are suspended in a liquid medium, such as a solution of nutrients or whole blood plasma;
The medium aids in the mass transfer mechanisms by which nutrients are transported to the cells and byproducts and wastes are returned from the cells into the bloodstream.

The structures of the invention take various forms. In one embodiment, the barrel is a thin rectangular container with an inlet and an outlet on opposite sides of shallow end walls. These ports are connected within the barrel by a porous membrane that creates a closed fluid flow path from one port to the other. The membrane may be coiled, looped, or folded into multiple folds to increase the length of the flow path from inlet to outlet. The membrane occupies only a portion of the internal volume of the torso; the rest of the volume creates a cavity in which living cells are placed. As a means of accessing this cavity, a penetrable, resilient, resealable plug is provided which seals the access hole in the wall of the shell. Fluid containing the cells is injected through the plug, such as with a hypodermic needle, into the cavity where the cells are placed. In use, the glandular structure is placed external to the patient's body, such as on the patient's wrist. It is attached to the wrist by adhesive tape or the like. A canyule is then attached to each inlet and outlet. Each canyule ends in a hollow needle that creates a pressure difference between them so that blood flows from one needle through the body to the other and then back into the body. Connected to blood vessels in the body. for example,
One needle is inserted into the patient's artery and the other needle is inserted into the patient's vein. This leads the artery into which the needle is inserted, to one port (inlet) of the barrel, then through the barrel along the fluid path formed by the membrane, and then to the other port (outlet). This creates a path for the blood to exit the vein and return directly to the vein where the other needle was inserted. As blood flows inside the membrane, it supplies nutrients to the cells in the cavities in the body outside the membrane, and removes both desirable byproducts and waste, such as insulin.
Remove the body for other use or disposal, as the case may be.

In another embodiment of the invention, the cellular material and blood flow paths are opposed. The cellular material of this example is enclosed in one or more closed pouches made of membrane and placed in a fluid-tight shell, while the blood enters the cavity in which the cells of the above example are placed. It flows around these sachets in corresponding cavities. Blood enters and exits the torso through the inlet and outlet as before. Inside the barrel is a resilient, resealable material that also seals the hole in the barrel and into which a hypodermic needle can be inserted through the barrel to fill the membrane pouch with cellular material. A rubber plug is provided as a means of accessing the interior of the barrel.

In a further embodiment of the invention, the cellular material is surrounded within a number of spheres made of porous membrane material. These balls are placed in a fluid-tight shell. The volume outside the bulb within the barrel is filled with a continuously varying flow of blood flowing between the inlet and outlet of the barrel. The barrel has a removable cover that provides access to its interior for containing the ball. This embodiment provides a very large surface area for each enclosed cellular material.

The body, of course, does not necessarily have to be rectangular; other shapes can also be used to advantage. Thus, in a further embodiment of the invention, the fluid-tight shell surrounding the membrane is cylindrical. The membrane is in the form of a closed cylindrical tube that is spirally wound into the barrel and exits at the top of the barrel. Blood flows from the inlet through the membrane tube to the outlet, transporting nutrients to the cellular material in the outer cavity of the tube in the body while removing desired by-products and waste from the cellular material to the bloodstream. carry it inside. As in the previous case, the hole extending through the wall of the barrel into the cavity in which the cells are placed is sealed fluid-tight. A perforated, resealable, sealing lid of resilient rubber or similar material provides access to the cavity in which the cells are placed.

Artificial gland structures having a relatively flat shape, as described above, have generally been found to be most convenient for attachment to the exterior of an animal's body. I mean,
This is because such a structure easily adapts to the human body if it is of an appropriate size. Moreover, the contact area between the torso structure and the human body is maximized by such a structure, and this improves the heat transfer between the human body and the torso. This is desirable since the temperature of the cells must be regulated to prevent cell destruction. For this reason, when the artificial glandular structure is attached to the exterior of the patient's body, a thermal covering is preferably placed over the artificial glandular structure to provide the required thermal environment. Such coverings may consist of multiple layers including at least one layer of a heat reflective material, such as aluminum, that is taped or otherwise adhered to a body part and exposed to body heat to create a thermal "pocket" surrounding the glandular structures. Easily made from cloth. Additionally, the torso structure is advantageously made of a thermally conductive material, such as stainless steel, which is relatively inert to body chemistry but has good thermal properties.

Nevertheless, the glandular structure of the present invention can be made in shapes other than the thin, flat format described above. Specifically, the shell structure can be made in the form of a cylinder containing cellular material and enclosing a number of closed cylindrical tubes stacked parallel in a cylindrical shell. Blood flows longitudinally along the axis of the torso from an inlet at one end to an outlet at the other, exchanging nutrients and substances as described above through gaps between overlapping cylindrical membrane pouches or tubes. do.

In a further embodiment, a single oval membrane pouch or tube is constructed within a cylindrical barrel. An inlet and an outlet are provided in the barrel, which connect the membrane tube to the blood flow. As the blood flows through the membrane tube, it washes the cellular material in the cylindrical cavity outside the tube within the body as described above.

These and other objects and features of the present invention will become better understood from the following detailed description of the invention taken in conjunction with the accompanying drawings.

The artificial glandular construct 10 shown in FIG. 1 is constructed from a fluid-tight, thin-walled body or housing 12 surrounding a porous membrane 14. Mouths 16 and 18 are
Holes 20 and 22 are provided extending through end walls 24 and 26 of housing 12. The membrane 14 is an elongated cylindrical tube whose sides are closed and whose end faces are open. It snaps neatly over the inner protrusions of the ports 16, 18 at both ends so that fluid enters the membrane tube 14 from the outside of the housing and exits the housing 12 through another hole 22. It is worshiped. cannulae 28, 30 each having hollow needles 32, 34 at their ends;
are connected to ports 16 and 18, respectively. These cannules are used to connect membrane 14 to blood flow as described below.

Bands 36, 38 are connected to the top surface of housing 12. These bands preferably have adhesive (not shown) on their undersides to securely attach housing 12 to the patient's body. A hole 42 extends through the housing 12 with a perforated, resilient, resealable lid 40 such as rubber.
is attached to the top and seals it. The lid 40 provides access to a cavity 44 in the shell forming part of the internal volume of the housing 12 outside the membrane 14. Cellular material placed within cavity 44 is injected through lid 40, such as with a hypodermic needle.

Housing 12 can be made from any material that is relatively inert to the cellular material placed therein. However, it is preferably made of a material such as stainless steel, which is relatively inert to the body's chemistry and which conducts heat relatively well, allowing body heat to easily transfer through it to the cellular material inside. . Of course, more elaborate devices can be used, such as incorporating heating wires into the housing 12 to regulate the temperature of the cellular material, but such methods are unnecessary in most cases. Housing 1 to prevent body heat from escaping
By coating 2 with a thermally insulating material as described above, the lifetime of the internal cellular material can be further controlled.

The size of the housing varies depending on the application. For example, when administering a product such as insulin to a diabetic patient, all external dimensions are approximately 50.8 mm (2 inches) long, 38.1 mm (11/2 inch) wide, and 9.5 mm (3/8 inch) high. ) has an internal volume of slightly more than 16.4 cubic centimeters (1 cubic inch), which can contain enough cells to achieve the intended purpose. A barrel thickness of 1.2 mm (3/64 inch) is adequate in most cases.

In use, the housing 12 is attached to the bands 36, 38.
It is rigidly attached to a part of the patient's body, such as the wrist, by other fixation devices. Then the needle 32
A blood vessel, such as an artery or vein, is inserted to draw blood into the membrane tube 14, and the needle 34 is inserted into another blood vessel, such as an artery or vein, at a lower pressure. Blood flows from one needle through a membrane tube to the other needle. Blood entering the housing 12 transports nutrients to the cellular material within the cavity 44. Blood exiting the housing carries the cells' beneficial by-products and waste products to distant locations for use or disposal, as the case may be. The tubular membrane 14 is porous, which allows nutrients, beneficial cellular by-products, and cellular waste to move through the membrane, but is more than a few microns in size and contains cellular material and glandular structures. It does not transfer materials such as antigens and antibodies that would cause harmful reactions in both connected bodies.

5-7, another embodiment of the present invention is shown therein. A rectangular body or housing 50 with ports 52, 54 connected to the end walls as shown includes a plurality of parallel, spaced, closed membrane pouches creating cavities filled with cellular material. It surrounds 56. Between each pouch 56 and between the pouch and the wall of barrel 50 there is a fluid passageway 60 leading to hollow holes 62, 64 in the center of ports 52, 54, respectively. Cannules 66 and 68 are connected to ports 52 and 54, respectively, for supplying and discharging blood to and from trunk 50 in the same manner as shown in FIG.

A pierced, resilient, resealable plug 70 extends into the membrane pouch 56 through a hole in the top wall of the barrel 50. Plug 70 is pierced with a hypodermic needle or the like to fill pouch 56 with cellular material after the glandular construct has been created and before its use.
Spacers (not shown) separate each pouch 56 to keep fluid passageways 60 open during use. The materials and use of the glandular structures of Figures 5-7 are similar to those of Figures 1-4 and will not be described in further detail.

The glandular structures described so far provide a substantial membrane surface at the interface between the blood stream, which carries nutrients and removes waste products, and the cellular material. Moreover, in the embodiments described so far, the cellular material can preferably be introduced after the housing has been closed or fluid-tightly sealed. Another embodiment that provides a larger membrane surface at the interface between blood flow and cellular material is shown in Figures 8-10. In this embodiment, the cellular material can most conveniently be placed before sealing the housing, thus resulting in a barrel with a tight-fitting eyelid cover.

The artificial gland structure shown in FIGS. 8-10 has a lower trunk 8
0 and a top surface 82 of the barrel removably engaged thereto. For purposes of illustration, the upper surface 82 is shown engaged to the lower barrel 80 by means of projections 84 on the two side edges of the upper surface that fit into corresponding grooves 86 in the lower barrel 80. There is a cavity 88 inside the body,
Therein, a porous membrane of the type described above is constructed to fluid-tightly surround the cellular material 92 therein. A large number of closed spheres 90 are placed. A cross-section of such a sphere is shown in FIG. Ports 94 and 96 are located in the lower body 80
holes 98 and 100 extending through the end walls of the. The canyules 102, 104 are the mouths 94, 96
are respectively connected to serve as fluid conduits for transporting fluid transport media, such as blood, to and from the cellular material within the membrane sphere 90. The upright posts 106, 108 are placed immediately in front of the corresponding holes in the interior of the lower barrel 80 to prevent the holes 98, 100 from being blocked by one or more balls 90. a strip 110 attached to the top wall 82;
112 connects the gland to the patient's body part in the same manner as described for the previous embodiment.

In use, the glandular structure of FIGS. 8-10 is placed externally on a patient's body part and the bands 110, 11
2 firmly attached to this body part by something else. A thermally insulating material can be placed over the glandular structure to provide a warm environment for the cellular material 92 within the glandular structure, thereby extending the life of the cellular material. Then Kanyur 102, 104
is connected to the patient's bloodstream in the same manner as described with respect to FIG. Connections can be made from artery to artery or vein to vein, provided a suitable pressure differential is maintained between the inlet and outlet to ensure fluid flow. However, since the arterial pressure is higher than the venous pressure, it is preferable to connect the artery to the vein, which ensures that the necessary pressure difference is maintained.

Blood flows from one cannula, such as cannula 102, into hole 98 and then into cavity 88 within the glandular structure. The blood washes over the sphere 90 containing cellular material and enters the cannula 104 through the hole 100, from where it returns to the body's bloodstream. As the blood washes over the bulb 90, it provides nutrients to the cellular material therein and provides desirable by-products (such as insulin if the cellular material includes cells or organ parts taken from organs such as the islets of Langerhans). ), as well as extracting cellular waste. These substances are transported into the body's bloodstream for use or disposal at distant locations.

The glandular structures shown in Figures 8-10 are particularly advantageous when the cellular material is to be renewed periodically. actual,
Blood flow to the structure can be temporarily stopped and the cellular material can be replaced while the glandular structure remains in place. This can be easily done by temporarily sealing the cannulae 102, 104, such as by gripping them.

Figures 11-13 show a circular artificial gland structure with a blood flow path formed by a spirally wound porous membrane. The glandular structure is the lower trunk 1
20 and a top surface 122 of the barrel that engages thereto for a fluid-tight seal. Mouth 124, 126
has holes 128 and 130 extending through the lower body 120 and upper surface 122, respectively. These ports provide fluid access to cavities 132 within the body 120 and surface 122. A tubular porous membrane 134 is spirally wound and extends from port 124 to port 126;
Fluid is then conveyed from hole 128 to hole 130. Vertical posts 136 keep membrane 134 in a fixed position. A resilient, resealable lid 138 on the top surface 122 of the glandular structure provides access to the cavity 132 for receiving cellular material. This preferably extends through the cavity 13 through the lid 138 and through the hole 140 therebelow.
This is done by inserting a hypodermic needle or the like into the tube.

As in the previous case, blood or other fluid-carrying media passing through the ports 124 and 126 "washes" the surrounding cellular material as it flows inside the membrane 134, thereby bringing necessary nutrients into the cavity 132. supply cellular material. Additionally, the fluid carries by-products and waste from the cellular material.

As mentioned above, it is preferred that the artificial glandular construct be constructed with a low and thin profile. This is because it fits snugly against the external surface of the body and also maximizes heat transfer from the body to the glandular structures. However, the glandular structure is not necessarily limited to this shape. Next, two other examples will be explained.

The gland structure shown in Figures 14-17 is a cylindrical tube 1.
50 and an end cap 152 providing a fluid-tight seal therein. The cap 152 is the cylinder 15
0 has a groove 154 into which a protrusion 156 fits to provide a fluid-tight seal. A mouth 158 with a hole 160 is made in the cap 152 and a mouth 162 with a hole 164 is made in the barrel 150. Cylinder 1
Inside 50 are cylindrical projections 166, 168. These protrusions serve as retaining rings for a number of elongated cylindrical closed tubes 170 of porous membrane material. Tube 170 creates a cavity containing cellular material. A gap 174 is created between each tube 170. These gaps are ports 158 and 16
A blood flow path is formed between the two. These channels surround the membrane tubes 170 and "wash" the tubes as the carrier fluid passes over them. membrane tube 17
Supply and discharge cavities 176 and 178 are created at each end of the cylindrical tube 150 to facilitate blood distribution. The glandular structures of Figures 14-17 are connected for blood flow in the same manner as described for the previous embodiments, so this point will not be discussed in further detail.

18-20, a modification of the embodiment shown in FIGS. 14-17 is shown therein. The cylindrical tube 190 has an end cap 192 sealed thereto along a seal line 194. A port 196 with a hole 198 is attached to the end cap 192 and a corresponding port 2 with a hole 202
00 is made on the cylinder 190. Oval porous membrane 204 is rigidly mounted within tube 190 at upper and lower contact surfaces 206a and 206b and connected at its ends to ports 196 and 200, respectively. Cannules 208 and 210 are attached to ports 196 and 200, respectively, and convey a fluid-carrying medium, such as blood, from hole 198 into the interior of membrane 204 and from hole 202 to cannula 210. As the blood passes through the interior of membrane 204, it "washes" the walls of this membrane, and the tube 190 and end cap 1
Nutrients are supplied to the cellular material within the cavity 212 created outside the membrane 204 inside the membrane 92 and by-products are removed therefrom. Hole 21 of tube 190
Resilient, pierceable, resealable plugs 214, 216 sealing 8,220 provide access to cavity 212. A hypodermic needle is inserted into plug 2 to inject cellular material into cavity 212.
It is inserted through 14,216. In use, the artificial gland of Figures 88-20 is connected to the patient's bloodstream as before.

It will be appreciated that the foregoing provides an artificial gland structure that is easily attached to the exterior of the patient's body and thus does not require surgical insertion. The structure is adapted for passage of a fluid transport medium, such as blood, therein to supply necessary nutrients to the cellular material therein and to remove both desired by-products and waste products from the cellular material.

Although the glandular construct has been described specifically in connection with the treatment of diabetic patients, it will be appreciated that it is not only used to compensate for a variety of sub-deficiencies in glandular function. Furthermore, although the structure is specifically adapted for use outside a patient's body, it can also be inserted inside the body. But this is not normal usage.

Structures can be made from a variety of materials, but
The material selected must be inert towards the fluid transport medium (blood) or cellular material as the case may be. Plastics such as polypropylene are easily and inexpensively formed into desired shapes;
It is advantageous for the structure. However, metals such as stainless steel are sometimes preferred due to their good heat transfer properties.

It will be understood that various changes may be made to the embodiments described above without departing from the spirit or scope of the invention.

[Brief explanation of the drawing]

FIG. 1 is a partially cut-away perspective view of a preferred embodiment of the invention; FIGS. 2, 3, and 4 are taken along lines 2-2, 3-3, and 4-4, respectively, of FIG. 5 is a perspective view of another embodiment of the invention, with a portion cut away to show the internal structure;
6 and 7 are lines 6-6 and 7- of FIG. 5, respectively.
FIG. 8 is a perspective view of a further embodiment of the invention, with a portion cut away to show the internal structure; FIG. 9 is a longitudinal cross-sectional view taken along line 9 of FIG. -9
10 is a longitudinal sectional view taken along line 10--10 of FIG. 8; FIG. 11 is a longitudinal sectional view taken along line 10-10 of FIG.
A perspective view of yet another embodiment of the invention incorporating a cylindrical barrel, with portions cut away for clarity, FIG. 12 is a cross-section taken along line 12--12 of FIG. 13 is a longitudinal cross-sectional view taken along line 13--13 of FIG. 12, and FIG.
FIG. 15 is a longitudinal cross-sectional view taken along line 15--15 of FIG. 14; , FIGS. 16 and 17 are longitudinal cross-sectional views taken along lines 16-16 and 17-17, respectively, of FIG. 15;
FIG. 18 is a perspective view of a variation of the structure shown in FIG. 14, partially cut away for clarity;
19 is a longitudinal cross-sectional view taken along line 19--19 of FIG. 18, and FIG. 20, line 2 of FIG.
FIG. 2 is a longitudinal cross-sectional view taken along line 0-20. 1st, 2nd, 4th, 5th, 6th, 7th, 8th, 9th, 11th, 1st
2, 13, 14, 15, 16, 17, 18, 1
Reference numeral 10 in Figures 9 and 20 indicates the "artificial gland structure" described in the claims, 12, 50, 80, 120, 1
50,190 is "fluid-tight shell", 14,56,9
0,134,170,204 is "membrane with many pores", 16,52,94,124,158,19
6 is "fluid inlet", 18, 54, 96, 126,
164,200 is "fluid outlet", 40,70,1
38,214 is "a member that allows access to the cavity where cells are placed", 44,56,90,132,1
Reference numerals 72 and 212 indicate a "void for confining cellular material", 60 a "fluid flow path", 82 a "removable wall portion", and 174 a "gap".

Claims (1)

[Scope of Claims] 1. An artificial glandular structure, which mainly comprises: A. A fluid-tight body having a fluid inlet and a fluid outlet directly connected to the human bloodstream, and B. Inside the body. a microporous membrane which, together with said body, defines a blood flow path and at least one cavity for entrapping living glandular cell material; is provided between the fluid inlet and fluid outlet of the torso for the passage of blood in contact with the membrane, the cavity being flushed only by blood so that the entrapped glandular cell material is free of physiological fluids in the bloodstream. C and secretes the products of the glandular cells only in the cavity; An artificial glandular structure that regulates secretions from the body into the bloodstream.