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TECHNICAL FIELD
This invention relates to a structure and method for providing a hormone
supply to a patient.
BACKGROUND OF THE INVENTION
Many diseases of the body are caused by a deficiency of certain endocrine
gland hormones. These diseases include myxedema and diabetes mellitus. The
endocrine glands are usually considered to include the thyroid,
parathyroid, thymus, pituitary, pineal, adrenal, pancreas and the gonads.
While a few hormones, e.g. thyroid hormone, may be taken orally, most
hormones are digestable and must be injected.
There are several disadvantages with periodic injection of hormones. Since
injections are painful and troublesome, and each injection represents a
possibility for infection, injections are spaced at intervals as far apart
as possible, resulting in peak and valley hormone concentrations. It has
been found that more effective treatment results from a constant supply of
hormones in accordance with the body's need. Constant control of the
hormone level avoids the problems of peaks and valleys in medication.
To date, the best known detector to measure the body's demand for a
particular hormone is the cell of the gland which produces that hormone.
Such a cell not only measures the body's need, but also produces the
necessary dosage of that hormone. The advantages of such cells are readily
apparent in the case of diabetes and insulin demand.
Diabetes mellitus is a disease characterized by hypoglycemia, polyuria, and
wasting. It is beneficial to maintain normal blood glucose levels in
diabetics at all times, an objective difficult or impossible to achieve
using insulin injection and diet. Two solutions have been suggested for
achieving more physiologic patterns of insulin replacement. One approach
uses a glucose sensor operably associated with an insulin injection
system. A second approach implants live insulin producing tissue within
the patient.
Transplantation of pancreatic tissue has met with limited success because
of immune rejection reactions encountered due to the difficulty in
obtaining a perfect tissue match. One solution to this problem is to
encapsulate live hormone-producing cells within a membrane capsule as
shown in U.S. Pat. No. 3,093,831 to Jordan. The membrane protects the
cells from such reactions but allows the free passage of hormones and
nutrients. The encapsulated hormone-producing cells can then either be
injected or surgically implanted. For various reasons encapsulated cells
once placed in the body only have a limited life span, usually measured in
weeks.
Other methods have been to place insulin cells on one side of a membrane
while blood flows on the other side of the membrane. However these devices
are for extracorporeal use which has limits on blood flow access and these
devices are not readily adaptable to implantation.
Since no means is presently known to keep implanted pancreatic cells alive
and producing insulin at a useful rate indefinitely, periodic replacement
is necessary. However, none of the previous implantable allows easy
replacement of the cells from outside the body. What is needed is a method
and structure for replacing live pancreatic islet cells or other
hormone-producing cells from outside the body without having to surgically
remove the entire implant.
This invention provides a system and method yielding an artificial
endocrine gland with replaceable hormone-producing cells. This invention
also provides a system and method yielding an artificial endocrine
pancreas which utilizes live pancreatic islet cells as the
hormone-producing cells.
SUMMARY OF THE INVENTION
The present invention discloses a method and structure for supplying a
patient with hormones in which he may be deficient. A hormone source, e.g.
hormone producing cells, a slow release hormone-containing composition, or
the like are placed in a housing implanted in the patient and those cells
may be replaced from outside the patient should the need arise. The
housing also allows the placement of a sensor and the release of hormones
into a patient from an external source while protecting the patient from
possible infection.
The housing comprises an impermeable hollow stem passing through a body
site such as the abdominal wall and a semipermeable membrane sack of
relatively large surface area attached to the stem and positioned inside
the patient, e.g., within the peritoneal cavity. The sack allows hormones,
nutrients, oxygen and waste products, to flow in and out of the housing
while preventing bacteria from entering the patient.
A sensor may be positioned in the sack for diagnostic or monitoring
purposes to measure properties of the patient's body fluid. Such a sensor,
a glucose level sensor, is disclosed in our pending application Ser. No.
218,710 filed Dec. 22, 1980 as a continuation-in-part of Ser. No. 107,965
filed Dec. 28, 1979. Because the fluid within the sack will have obtained
equilibrium with the patient's body fluid, the sensor is capable of making
the same measurements as if it had been located directly within the body
cavity. Should the sensor fail for any reason, it can easily be removed
and replaced without the threat of infection to the patient. Additionally,
a catheter for releasing a hormone such as insulin may have its end
located within the sack. Insulin would then be released into the sack and
diffuse out through the walls of the sack and into the patient. This
protects the patient from possible contamination caused by the bacteria
which may accidentally become present within the insulin.
Alternatively, hormone producing cells may be removably placed in the sack.
The cells take over the function of the corresponding natural gland, sense
the amount of hormone needed, and produce the correct amount of the
desired hormone. The hormone passes through the semipermeable membrane
into the patient's body fluids while nutrients, oxygen and in some cases
other hormones, pass from the body fluids through the semipermeable
membrane to the hormone producing cells. Since an exchange of hormones may
take place in both directions through the membrane, the body itself
regulates the course of hormone production as with a natural gland.
The present invention is especially useful in the treatment of diabetes
where effective control of insulin and glucose levels has proved
difficult. Because the semipermeable membrane sack prevents the passage of
immune response bodies, it not only allows the use of live cells taken
from another human lacking a perfect tissue match, but also the use of
live pancreatic cells taken from other animals.
Numerous other features of the present invention will become readily
apparent from the following detailed description of the invention and
embodiments, from the claims and from the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
In the accompanying drawings forming part of the disclosure:
FIG. 1 is a cross-sectional view of a sensor, catheter, and housing
comprising a stem and sack shown implanted in a patient;
FIG. 2 is a cross-sectional, elevational view showing an alternative
housing having a generally flat disc-like sack and coaxial inlet and
outlet stem members;
FIG. 3 is a bottom view of the embodiment shown in FIG. 2 showing heat
sealed ribs reinforcing the structure of the housing;
FIG. 4 is an embodiment similar to FIG. 1, but having two stems and a
plurality of membrane tubes within the patient;
FIG. 5 is a cross-sectional view taken along plane 5--5 of FIG. 4 showing
the positioning of the tubes;
FIG. 6 is an enlarged view of one of the tubes showing spacing filaments
wound about the tube; and
FIG. 7 is an embodiment similar to FIG. 4, but having a generally flat
membrane tube with two stems.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
While this invention is susceptible to embodiment of many different forms,
there are shown in the drawings and will be described in detail, preferred
embodiments of the invention. It should be understood that the present
disclosure is to be considered as an exemplification of the principles of
the invention and is not intended to limit the invention to the
embodiments illustrated.
The precise shapes and sizes of the components described are not essential
to the invention unless otherwise indicated. For ease of description, the
device of this invention will be described in its normal operating
position and such terms as up, down, inside, outside, etc. will be used
with reference to this position. The choice of materials is dependent upon
the particular application involved and other variables as those skilled
in the art will appreciate. The materials have to be physiologically
compatible with the patient.
Referring now to the drawings, FIG. 1 shows a housing 10 for placement in
the patient. The housing 10 is constituted by an impermeable hollow stem
14 and a semipermeable membrane sack 15. The hollow stem has a distal end
17 defining an extracorporeal segment 18 and a proximal end 20 defining a
subcutaneous segment 21. The sack 15 is adapted to receive a hormone
source, e.g., live hormone-producing cells and has an access opening 22
which is coupled to the proximal end 20 of the hollow stem 14. The stem 14
defines an access passageway to the sack 15. A seal means such as plug 30
seals the distal end 17 of the stem 14. Although the sack 15 is shown to
have a generally tubular shape, it is understood that the sack may have
any suitable configuration including a generally hollow disk shape.
The housing 10 is surgically implanted in a patient through the abdominal
wall. The abdominal wall 12 is shown here to have an epidermis 24,
subcutaneous fat 25, fascia 26 and a peritoneal membrane 27. Peritoneal
fluid surrounds the sack 15 of the implanted housing 10. The distal end 17
of the hollow stem 14 has a flexible zone 28 comprising a plurality of
circumferential grooves and extends beyond the body of the patient
allowing access to the sack 15 through the hollow stem 14 from outside the
body. Preferably, a portion of the subcutaneous segment 21 for placement
in the subcutaneous fat 25 is surrounded by one or more porous cuffs 29
which promote ingrowth of tissue to help anchor the stem and help prevent
infection. It is more preferred that at least two cuffs be used, and that
there be some distance between cuffs to further increase the area for
ingrowth of tissue and to decrease the possibility of infection.
Implantation of such an access stem is discussed by Tenckhoff et al., "A
Bacteriologically Safe Peritoneal Access Device," Trans. Amer. Soc. Artif.
Int. Organs 14:181 (1968) which is incorporated by reference to the extent
pertinent.
Also shown in FIG. 1 is a sensor 31 attached to a transmission line 32. The
sensor 31 may be any type of sensor to determine any body function or
condition, but preferably is an osmolality sensor for the determination of
glucose levels as disclosed in our copending application Ser. No. 218,710
filed Dec. 22, 1980 and incorporated by reference. Such a sensor may be
operably associated with a control device (not shown) which would regulate
the release of medication such as a hormone into the membrane sack 15
through cannula 35.
The patient is protected should any bacteria or other foreign matter
somehow enter the sack. Only the medication can pass through the small
pores of the membrane sack 15. The membrane material of this sack is
discussed in more detail below. In place of or together with the sensor
and cannula, live hormone producing cells may be placed in the sack 15.
An alternative housing 110 having a disc-like sack 115 providing a large
surface area for hormone transfer is shown in FIG. 2. The stem 114
comprises an inner stem member 140 within an outer stem member 142,
surrounding part of the outer stem member 142 is at least one, preferably
two, porous cuffs 129. The stem members are preferably coaxial and jointly
closed by a single closure unit such as plug 144.
Located within the disc-shaped sack 115 is a separating wall plate 146
attached to the inner stem member 140. The separating wall plate 146
divides the interior space or chamber of the sack 115 into a first chamber
section 148 and a second chamber section 150. As hormone producing cells
are introduced under slight pressure through the interior stem member 140,
they pass into the first chamber section 148 then about the periphery of
the separating wall plate 146 and into the second chamber section 150.
This ensures that hormone producing cells are evenly distributed
throughout the sack 115 and a flow-through passage is created by the
separating wall plate 146. This provides an even distribution over a large
surface area and insures an efficient transfer of hormones and nutrients
into and out of the housing 110.
To reinforce the sack 115, a plurality of sealing connections 152 may be
made between the walls of the sack and the separating wall plate 146.
(FIG. 3). The separating wall plate 146 may also be provided with ridges
154. The ridges 154 and sealing connections 152 add strength to the
housing 110 and insure an open flow path across the surface of the
disc-like sack 115. The connections 152 also maintain a set thickness to
the chamber sections 148 and 150 to insure that cells located in the
housing 110 are not far from the surface of the sack 115. Generally the
chamber sections 148 and 150 have a thickness of about 0.5 millimeters to
about 5 millimeters. The overall diameter of sack 115 is about 50 to about
150 millimeters.
In a further preferred embodiment shown in FIGS. 4-6, the housing 210
generally comprises two stems 214 in fluid communication with a bundle of
tubes 215. Each stem has a distal end 217 defining an extracorporeal
segment 218 and a proximal end 220 defining a subcutaneous segment 221.
Seal means such as plugs 230 seal the distal ends 217. Preferably each
tube 215 constituting the bundle has an inside diameter from about 200
microns to about 1,000 microns. The tubes are preferably are spaced from
one another and connected by a flow-dividing unit 260 which places the
tubes in a sealed fluid communication with the stems 214. The dividing
unit 260 may be constructed using principles well-known in the dialysis
art. Illustrative of such a method is disclosed in U.S. Pat. No. 3,708,071
to Crowley, incorporated herein by reference to the extent pertinent.
As many as a hundred tubes 215 may be used in a bundle according to this
embodiment. Although the flow dividing unit 260 is shown with a generally
circular cross-section in FIG. 5, this unit and hence the positioning of
the tubes 215 may have any appropriate cross-section including generally
rectangular or eliptical.
Preferably, some of the tubes, or more preferably all of the tubes, are
provided with a spacer means such as a filament 262 wound helically about
the tube as shown in FIG. 6. This maintains the space between tubes to aid
the free flow of body fluids through and about the tubes. Such flow is
desirable to ensure that there is a constant flow of nutrients, oxygen and
hormones into and out of the housing 210.
As with the other embodiments, each of the access stems 214 of the
embodiment shown in FIG. 4 preferably is provided with two porous cuffs
229 which are spaced to allow the in-growth of tissue to help prevent
infection and to hold the housing 210 in place.
Another embodiment similar to that of FIG. 4 is shown in FIG. 7. A single
tube 315 with a generally broad, flattened construction is provided. The
tube 315 is in fluid communication with the proximal ends 320 of two
access stems 314 which have plugs 330 removably mounted on their distal
ends 318 and provides a hormone transfer. This embodiment is preferably
provided with a plurality of porous cuffs 329 on each of the access stems.
The broad, flattened tube 315 may be reinforced with ribs 352 which may be
formed by heat sealing the two opposite walls of the tube along linear
portions. The tube 315 preferably has a width across its broad section of
about 75 milimeters and a thickness of about 1-5 millimeters.
The advantage of the embodiments shown in FIGS. 4-7 is that there are two
access passageways which allow the insertion and removal of hormone
producing cells into their respective tubes. It is easier to place and
remove cells by applying a small pressure at one stem, while introducing a
small vacuum at the other. This effectively sweeps out the old cells which
are no longer functioning properly and allows easier replacement with new
viable cells.
In the embodiments illustrated, either a combination of sensor and a
hormone releasing cannula may be located within the housings or hormone
producing cells may be placed in the housing. These hormone producing
cells can be taken from an organ such as the pancreas that produces the
desired hormone. Alternatively genetically altered bacteria may be used.
Hormone producing cells may be prepared by growing in culture to obtain a
relatively pure source of cells. One such method is disclosed by Chick et
al., "Pancreatic Beta Cell Culture: Preparation of Purified Monolayers"
Endo 96:637 (1975) incorporated by reference to the extent pertinent.
Alternatively the cells may be removed from a fresh organ. The cells are
then suspended in solution and placed into the housing.
Instead of a suspension of cells, microencapsulated live hormone producing
cells surrounded by semi-permeable membrane may be used. Each microcapsule
has a diameter of approximately 100-300 microns, allowing a plurality of
such microcapsules to be placed in the housing. Because of their small
size, the microcapsules have a high surface area to volume ratio allowing
ready access of nutrients and oxygen to the cells and dispersal of the
hormone produced and waste products from the cells. A method of producing
such microencapsulated cells is disclosed, by Lim et al.,
"Microencapsulated Islets As Bio-Artificial Endocrine Pancreas", Science
210:908 (1980) and is incorporated herein by reference to the extent
pertinent.
Many materials can be used to form the membrane sacks and tubes. Examples
of suitable materials are cellulose, cellulose hydrate, cellulose acetate,
various cellulose esters, polycarbonate membranes of the type disclosed in
U.S. Pat. Nos. 4,075,108 and 4,160,791 to Higley et al., poly(vinyl
alcohol) membranes of the type described in U.S. Pat. No. 4,073,733 to
Yamauchi et al., microporous poly(ethylene) and poly(propylene) films,
cross linked alginate (a non-toxic polysaccharide),
poly(2-hydroxyethylmethacrylate) and poly(2,3-dihydroxypropylmethacrylate)
films, and the like. The preparation of such membranes is disclosed in
U.S. Pat. No. 4,075,092 to White et al., Klomp et al., "Hydrogels for
Encapsulation of Pancreatic Islet Cells", Trans. Amer. Soc. Artif. Int.
Organs 25:74 (1979), Lim et al., "Microencapsulated Islets as
Bioartificial Endrocine Pancreas" Science 210:908 (1980), and Lee et al.,
Handbook of Biomedical Plastics, Pasadena Technology Press, Pasadena,
California (1971). All of the foregoing references are incorporated herein
by reference to the extent pertinent. PAN (a polyacrylonitrile membrane
available from Rhone-Ponlanc) may also be used. Polycarbonate membranes
are particularly advantageous because they are heat sealable and are
entirely nonbiodegradable. This allows easy construction and a long life
span. One such polycarbonate membrane is BARD PCM available from C. R.
Bard, Inc.
A membrane-like filter can be used in place of the membrane. Such a filter,
disclosed in U.S. Pat. No. 4,141,838 to Schilling and incorporated by
reference to the extent pertinent, allows the passage of nutrients, oxygen
and hormones and prevents the passage of bacteria and large proteins.
The membrane material chosen may then be treated with heparin to minimize
deposits of fibrin in a manner known to those skilled in the art.
Illustrative such treatments is the method disclosed in U.S. Pat. No.
3,441,142 to Oja, incorporated by reference to the extent pertinent.
The choice of the material for the sack or tube depends on several factors.
There should be permeability for desirable molecules such as nutrients,
oxygen and hormones, and impermeability to undesirable elements such as
bacteria and possibly immune response elements. To prevent the passage of
bacteria the membrane should have an effective pore size less than about
0.5 microns. It is preferred that the membrane be impermeable to such
immune response bodies as immunoglobulins which have molecular weights
greater than 50,000 to 150,000 daltons. Such a membrane would then have a
pore size of approximately 40-50 Angstroms. This allows the passage of
nutrients which generally have molecular weights less than 200, as well as
the passage of hormones such as insulin which has a molecular weight of
approximately 6400, and prevents the passage of bacteria which may be
accidentally introduced within the device. In general, it is desirable
that the pores be as large as possible, allowing a free flow of nutrients
and hormones while still protecting the patient.
To facilitate the transfer of nutrients and hormones, it is desirable that
the membrane have a thickness of 200 microns or less. However, membranes
of thickness as low as 20 microns can be used as long as they exhibit
suitable permeability and adequate strength. The exterior surface of the
membrane sack or tube can be reinforced with an open mesh made of
polyethylene or the like to add resiliency, strength, and resistance to
breakage. The sack or tube membrane preferably is treated with heparin to
decrease formation of fibrin on the outside surface in contact with the
peritoneal fluid.
The foregoing specification is intended as illustrative and is not to be
taken as limiting. Still other variations within the spirit and scope of
this invention are possible and will readily present themselves to those
skilled in the art.
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