 |
Description  |
|
|
TECHNICAL FIELD
This invention relates to artificial hormone-producing glands and more
particularly to a structure and method for replaceably implanting live
hormone-producing cells within 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. However an effective glucose sensor has yet to be developed for
general use. 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. 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 and depend on blood flow access. 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 devices allow for
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 from implanted hormone
producing cells and allowing those cells to be replaced from outside the
patient should the need arise.
This is accomplished by implanting in the patient a suitable housing
comprising an impermeable hollow stem passing through a body site such as
the abdominal wall and a semipermeable membrane sack 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.
The sack may be reinforced by an outer mesh of physiologically compatible
material. Live hormone producing cells are contained in a semipermeable
membrane envelope positioned within the semipermeable sack. The envelope
is permeable to nutrients and hormones, but is impermeable to the
hormone-producing cells and immune response bodies.
The implanted 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. A genetically altered
organism may also be used for this purpose.
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 housing shown implanted in a patient;
FIG. 2 is an enlarged plan view of a replaceable envelope having a toroidal
configuration;
FIG. 3 is a greatly enlarged cross-sectional view of microencapsulated live
hormone-producing cells;
FIG. 4 is a fragmentary cut-away view, partly in section, of a replaceable
envelope collar showing a connecting means associated with a plug;
FIG. 5 is a fragmentary cross-sectional view, including an enlarged
portion, and showing the replaceable envelope collar as positioned within
the housing;
FIG. 6 is a cross-sectional view taken along plane 6--6 of FIG. 5 showing
the housing and envelope;
FIG. 7 is a cross-sectional view of another preferred embodiment of the
housing having two access ports outside the patient;
FIG. 8 is a cross-sectional view of yet another preferred embodiment
similar to FIG. 7 except the two access ports are adjacent; and
FIG. 9 is a cross-sectional view taken along plane 9--9 of FIG. 8.
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, e.g., peritoneal, segment 21. The sack 15 is adapted to
receive an envelope containing live hormone-producing cells and has an
access opening 22 which is coupled to the proximal end 20 of the hollow
stem 14. Sack 15 may be reinforced on the outside by a reinforcing means
such as mesh 16. The stem 14 defines an access passageway to the sack 15.
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 flat 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 defines a normally closed access opening and 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.
A replaceable envelope containing live hormone-producing cells is received
through the hollow stem 14 and into the sack 15. A seal means is then
placed over the distal end 17 of the hollow stem to seal the housing. The
replaceable envelope can be removed by a similar process. As it is
removed, the envelope contacts the camming surfaces 31 of the hollow stem
14 which help collapse the replaceable envelope to facilitate its removal.
One preferred configuration for the replaceable envelope is toroidal
envelope 33 as shown in FIG. 2. The toroidal envelope 33 comprises a
semipermeable membrane tube 34 retaining live hormone producing cells
within the tube. A withdrawal tab 35 connected to the envelope 33 allows
the use of forceps (not shown) or a like implement to insert and remove
the envelope from outside the body. A length of monofilament line may also
be attached to the withdrawal tab 35. The structure and composition of the
membrane will be discussed in greater detail below.
Another preferred configuration for the envelope is shown in FIG. 3. Here
the membrane envelope comprises microencapsulated live hormone-producing
cells 37 surrounded by a semipermeable membrane 38. Each microcapsule 36
has a diameter of approximately 100-300 microns, allowing a plurality of
such microcapsules to be placed in the sack 15. Because of their small
size, the microcapsules 36 have a high surface area to volume ratio
allowing ready access of nutrients and oxygen to the cells 37 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 by reference to the extent
pertinent.
A further preferred envelope configuration is set forth in FIGS. 4-6 and
includes a flexible envelope collar 41 defining an open slot 42. The
collar 41 has a first end 46 and is comprised of an inner membrane 43 and
an outer membrane 44 which encase a substantially unicellular layer of
live hormone-producing cells 45. A substantially unicellular layer i.e., a
monolayer of live cells completely covering the membrane to a depth of one
cell, is employed for two reasons: first to provide maximum surface area
to volume ratio and second to discourage de-differentiation of the cells.
Effective preparation of a insulin-producing monolayer comprising mostly
Beta cells is disclosed by Chick et al., "Pancreatic Beta Cell Culture:
Preparation of Purified Monolayers", Endo 96:637 (1975). Using techniques
well known to those in the art, either the inner or outer membrane or
both, are treated or placed in contact with the live cells until cell
attachment forms a substantially unicellular layer on that surface.
However, it is not essential that the cells be in a unicellular or
monocellular layer as long as diffusion of nutrients and hormones is
possible to and from the cells.
The seal means, a plug 48, is used to seal the distal end 17 of the hollow
stem 14. The plug 48 is multifaceted to inhibit bacteria from entering the
housing 10. The plug 48 may be linked to any one of the replaceable
envelopes by a connecting means such as a monofilament line 49 to aid in
the removal of an envelope from the housing 10. In use with the envelope
collar 41, the connecting means can also include a collar collapsing means
51 which comprises segments of monofilament lines 52 or the like attached
to the envelope collar 41 at attachment points 54 near the open slot 42 in
the collar 41. The line segments 52 are then attached to the monofilament
line 49 which in turn passes through a ring or tube segment 55 attached to
the inner membrane 43 of the envelope collar 41 approximately opposite the
slot 42.
As tension is placed upon the monofilament line 49, the slot 42 is closed
and the collar 41 is partially collapsed, its diameter reduced, to
facilitate easy removal from the sack 15. It is advantageous that the
attachment points 54 be placed approximately mid-length along the envelope
41 or slightly toward the first end 46 from mid-length. This allows the
collar 41 to become tapered when collapsed, the first end 46 becoming the
smallest, to aid in removing the collar from the housing 10. In the event
envelope 41 binds against the hollow stem during removal, additional
tension on lines 49, 51 and 52 will collapse envelope 41 further.
As can be seen in FIGS. 5 and 6, the flexible envelope collar fits snugly
within the sack 15 to minimize the distance nutrients and hormones would
have to pass to and from the peritoneal fluid. This snug fit is maintained
by the natural resiliency of the collar 41 as it expands against the sack
15. Minimizing the distance nutrients and hormones have to pass helps
maintain the cells in a viable condition and allows for a faster response
time, i.e. it takes less time for the patient's hormone need to be
communicated to the cells and for the hormone produced to be released in
the body. The membrane sack 15 may also be filled with a nutrient fluid 59
to help keep the hormone-producing cells alive.
Instead of a housing it is also possible to use a loop or hose as shown in
FIG. 7. The hose 70 comprises a tube 71 and two, impermeable membrane
hollow stems 72, each being like the stem 14 shown in FIG. 1. The membrane
envelope may be inserted or removed through either stem. This simplifies
placement and removal of the envelope and allows easier maintenance of the
inside of the implant. The inside of the hose 70 may be swabbed with an
antiseptic during replacement of the envelope.
The access stems of FIG. 7 can be fused into one common region as shown in
FIGS. 8 and 9. Such a combination stem 75 having two passageways 76 enters
the body at one site only. Each passageway is connected to each end of the
tube 77 in a manner similar to that shown in FIG. 7 providing a loop that
allows placement or removal of the envelope through either end. By having
both passageways pass through the same site, the possibility of infection
is further reduced.
Many materials can be used to form the membrane sack 15, the envelopes, and
the 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, Calif. (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 herein
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 herein 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. Generally, pore sizes from
about 1.0 to 0.025 microns can be employed, a preferred size being
approximately 0.5 microns. 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. If desired, a membrane size of approximately
0.025 microns can be used to prevent the passage of viruses. 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 90 (FIG. 7) 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 envelope membrane is constructed in the same manner as the sack or tube
membrane. It is preferred that the envelope membrane be impermeable to
such immune response bodies as immunoglobulins which have molecular
weights greater than 150,000. Such a membrane would then have a pore size
of approximately 50 Angstroms. This is particularly appropriate in view of
the fact that some diabetics have antibodies which may react with the
islet cells. See, for example, Dobersen et al. "Cytotoxic Autoantibodies
to Beta Cells in the Serum of Patients with Insulin Dependent Diabetes
Mellitus", N.E. Journ. Med. 303:1493 (1980).
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.
* * * * *
|
|
 |
|
 |
Description |
|
