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Description  |
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The present invention relates to an open loop implantable medication
infusion system with a feedback control option. In a preferred embodiment,
the invention is directed to an implantable insulin delivery system for
diabetics, although the invention is not limited thereto.
Certain human disorders, such as diabetes, require the injection into the
body of prescribed amounts of medication at prescribed times or in
response to particular conditions or events. Various kinds of infusion
pumps have been propounded for infusing drugs or other chemicals or
solutions into the body at continuous rates or measured dosages. Examples
of such known infusion pumps and dispensing devices are found in U.S. Pat.
Nos 3,731,861; 3,692,027; 3,923,060; 4,003,379; 3,951,147; 4,193,397;
4,221,219 and 4,258,711. Some of the known pumps are external and inject
the drugs or other medication into the body via a catheter, but the
preferred pumps are those which are fully implantable in the human body.
Implantable pumps have been used in infusion systems such as those
disclosed in U.S. Pat. Nos. 4,077,405; 4,282,872; 4,270,532; 4,360,019 and
4,373,527. Such infusion systems are of the open loop type. That is, the
systems are pre-programmed to deliver a desired rate of infusion. The rate
of infusion may be programmed to vary with time and the particular
patient. A major disadvantage of such open loop systems is that they are
not responsive to the current condition of the patient, i.e. they do not
have feedback information. Thus, an infusion system of the open loop type
may continue dispensing medication according to its pre-programmed rate or
profile when, in fact, it may not be needed.
There are known closed loop infusion systems which are designed to control
a particular condition of the body, e.g. the blood glucose concentration.
Such systems use feedback control continuously, i.e. the patient's blood
is withdrawn via an intravenous catheter and analysed continuously and a
computer output signal is derived from the actual blood glucose
concentration to drive a pump which infuses insulin at a rate
corresponding to the signal. The known closed loop systems suffer from
several disadvantages. First, since they monitor the blood glucose
concentration continuously they are complex and relatively bulky systems
external to the patient, and restrict the movement of the patient. Such
systems are suitable only for hospital bedside applications for short
periods of time and require highly trained operating staff. Further, some
of the known closed loop systems do not allow for manually input
overriding commands. Examples of closed loop systems are found in U.S.
Pat. Nos. 4,055,175; 4,151,845 and 4,245,634.
An implanted closed loop system with some degree of external control is
disclosed in U.S. Pat. No 4,146,029. In that system, a sensor (either
implanted or external) is arranged on the body to sense some kind of
physiological, chemical, electrical or other condition at a particular
site and produced data which corresponds to the sensed condition at the
sensed site. This data is fed directly to an implanted microprocessor
controlled medication dispensing device. A predetermined amount of
medication is dispensed in response to the sensed condition according to a
pre-programmed algorithm in the microprocessor control unit. An
extra-corporeal coding pulse transmitter is provided for selecting between
different algorithms in the microprocessor control unit. The system of
U.S. Pat. No. 4,146,029 is suitable for use in treating only certain
ailments such as cardiac conditions. It is unsuitable as a blood glucose
control system for example, since (i) it is not practicable to measure the
blood glucose concentration continuously with an implanted sensor and (ii)
the known system is incapable of dispensing discrete doses of insulin in
response to certain events, such as meals and exercise. Furthermore, there
are several disadvantages to internal sensors; namely, due to drift, lack
of regular calibration and limited life, internal sensors do not have high
long-term reliability. If an external sensor is used with the system of US
Patent No. 4,146,029, the output of the sensor must be fed through the
patient's skin to the implanted mechanism. There are inherent
disadvantages to such a system, namely the high risk of infection. Since
the algorithms which control the rate of infusion are programmed into the
implanted unit, it is not possible to upgrade these algorithms without
surgery. The extra-corporeal controller merely selects a particular one of
several medication programs but cannot actually alter a program.
It is an object of the present invention to overcome, or substantially
ameliorate the above described disadvantages of the prior art by providing
an implantable open loop medication infusion system with a feedback
control option.
Accordingly, in its broadest form, the present invention provides an
implantable medication infusion system comprising an implantable unit for
controllably dispensing medication into the body; an external controller
adapted to communicate with said implantable device when implanted via a
telemetry link, and sensor means for sensing a condition of the body such
as temperature, heart rate, skin resistivity or blood glucose level, the
output of said sensor being connected to said external controller.
It is to be noted that in the present invention, the output of the sensor
means is fed to the external controller. The sensed data is processed in
the external controller which then transmits appropriate signals to the
implanted device to infuse the appropriate dosage.
Typically, the implanted unit infuses medication in accordance with a
preselected profile which can be determined from the patient's history,
i.e. the system normally functions as an open loop system. However, at
intermittent times, the condition of the patient can be sensed and fed to
the external controller which, in turn, overrides the predetermined
profile to vary the dosage as required.
The external controller is programmed to adapt to the particular patient by
monitoring the sensed conditions of the patient in response to different
times and dosages of medication. Thus, by suitable programming, the system
is self-learning and adaptive. Further, from past performance of the
particular patient, the system can suggest the times at which further
readings should be taken after a particular dosage is given so as to give
a true and faithful indication of the actual condition of the patient.
The program in the external controller can be updated without the
requirement of surgery. Moreover, the sensor can be checked and calibrated
to ensure that it is oprating properly.
In a preferred embodiment, the implantable medication delivery system
comprises an implantable unit with a refillable reservoir, a catheter
connected thereto, and a pumping mechanism activated by a microcomputer or
microprocessor for pumping medication from the reservoir through the
catheter into the body. The implantable medication unit receives
information and control commands via a telemetry link from an external
controller unit having a microprocessor. The external controller receives
feedback in the form of intermittent sampling of blood using enzyme strips
and a reflectance meter and/or additional sensor(s) which measure(s)
physiological parameter(s) such as heart rate or blood pressure or
temperature or skin resistivity. The feedback information is processed by
the external unit in accordance with a mathematical model of the patient
and the relevant parameters are transmitted to the implanted unit which
adjusts its delivery profile according to a prescribed algorithm. The
external unit can also detect an alarm condition and take appropriate
steps, e.g. abort infusion.
Notwithstanding other forms of the invention, preferred embodiments thereof
will now be described with reference to the drawings in which:
FIG. 1 is a schematic view of the system of the preferred embodiment;
FIG. 2 is a block diagram of the system of FIG. 1;
FIG. 3 is a schematic block diagram of the reflectance meter of FIG. 2;
FIG. 4 is a schematic cross sectional view of the refilling port of FIG. 2;
FIG. 5 is a schematic diagram of another embodiment of a pumping mechanism
suitable for use with the implanted unit of FIG. 2;
FIGS. 6A is a schematic front cross sectional view of the gating
arrangement of the reflectance meter of FIGS. 2 and 3;
FIG. 6B is a schematic side cross sectional view of the gating arrangement
of the reflectance meter of FIGS. 2 and 3;
FIG. 7A is a cross sectional view of a catheter suitable for use with the
implanted unit of FIG. 2.
FIG. 7B is a plan view of the end of the catheter of FIG. 7A;
FIG. 8 is a schematic plan view of a reservoir flushing system suitable for
use with the implanted unit of FIG. 1;
FIG. 9 is a schematic diagram of the hydraulics of the flushing system of
FIG. 8; and
FIG. 10 is a cross-sectional view of a catheter of the flushing system of
FIG. 8.
The implantable medication system of the preferred embodiment comprises the
following major sub-systems shown in FIG. 1; an external controller 1, an
enzyme test strip 2 for use in determining the blood glucose concentration
and an implantable unit 3. It may also comprise a sensor 30 (FIG. 2) for
sensing physiological conditions such as heart rate and blood pressure,
temperature, skin resistivity or any other relevant body condition.
The implantable unit 3 comprises a reservoir 4 separated by a diaphragm 5
from a liquid/vapour chamber 63 saturated with freon 113 which maintains
the reservoir at a pressure equilibrium less than atmospheric pressure,
provided that the system is kept at body temperature. Freon 113 has a
linear pressure characteristic from -4 psig (at 90.degree. F.) to
approximately -2.5 psig (at 104.degree. F.). Using freon 113, the
medication reservoir 4 will be maintained at a pressure below that of the
human body pressure up to altitudes of 8,500 ft. For patients who may live
above that altitude, other fluorocarbons at lower pressure may be
employed. In this way, should there be a leak from the reservoir, the
effect would be to cause body fluids to diffuse slowly into the reservoir
4 rather than to have a rapid flow of medication enter into the body where
it could harm the patient. Because of the pressure differential between
the body and the medication reservoir 4 the medication will not flow from
the reservoir 4 into the body. As the amount of medication in the
reservoir 4 varies, the flexible diaphragm 5 moves up or down, with the
freon 113 being converted either from liquid to vapour or vapour to liquid
to provide an essentially constant pressure which will always be below one
atmosphere and below normal body pressure.
The reservoir 4 can be refilled percutaneously with a syringe. As shown in
FIG. 4, a self-sealing refilling port 9 is provided for this purpose. The
refilling port 9 is made out of an elastomer 47 such as silicon rubber
surrounding a gel sealant 48. The fluid is injected by the syringe (not
shown) which pierces the elastomer 47 and the gel 48. The holes left by
the syringe in the elastomer 47 will be filled by the high viscosity gel
48. Thus, the refilling port may be used many times over. The tip of the
syringe is stopped by a metallic strainer 49 which in addition prevents
any solid debris from entering the reservoir 4. The injected fluid then
passes through a filter in the form of a porous foam plug 50 in order to
prevent any large air bubbles and fibril aggregates entering the system.
Typically, the reservoir 4 and syringe have inner surfaces of medication
compatible material e.g. hydrophilic material.
The entry to the reservoir 4 is also protected by a check valve 52 (FIG. 2)
for preventing leaks back into or out from the refilling port 9, and
another check valve 12 for preventing similar leaks from a pumping
mechanism 8 which pumps the medication from the reservoir 4 through a
catheter 6 into a desired site in the body.
The implantable unit 3 is powered by a lithium battery 7 and the pumping
parameters are controlled and monitored by an electronics circuit 10. The
above elements are hermitically sealed within a titanium case 60 to
protect them from any adverse effects by body fluids. The controller unit
1 is kept outside the patient body. The function of the external
controller unit 1 is to calculate the required medication infusion regimen
and serve as a communication link between the patient/physician and the
implantable delivery unit 3. Furthermore, it serves to close the loop by
sampling the blood glucose level through glucose test strips 2, or sensor
30 which may monitor blood pressure, heart rate or act as a needle type
glucose sensor which can be inserted subcutaneously.
FIG. 2 illustrates the mechanical and electrical arrangements of the system
in block diagrams. The medication fluid is refilled through the
self-sealing port 9 into the reservoir 4 which is connected to the pumping
mechanism , such as a solenoid activated reciprocating piston. The pumping
mechanism 8 has inlet and outlet check valves 12, 13 to minimize
back-flow. Typically, each stroke of the reciprocating piston will
displace a volume of 0.1 microlitre of medication fluid. Any known
suitable pump, such as those described in the prior art patents referred
to above, can be used. An alternative pumping mechanism is shown in FIG.
5. In this arrangement, the reservoir chamber 58 is arranged as disclosed
in U.S. Pat. No. 3,731,681 where the reservoir 58 is maintained above
arterial pressure. The pumping is achieved by opening an inlet solenoid
valve 54 which allows the fluid to flow into chamber 56 as the pressure in
this chamber (P.sub.2) is less than the pressure (P.sub.1) of reservoir
58. Valve 54 is then shut and solenoid valve 55 is opened to enable the
fluid in the chamber 56 to be displaced by a resilient flexible membrane
59 which had been subject to pressure P.sub.1 and now returns to its
resting position. To complete the cycle and prepare the mechanism for the
next pumping cycle, the valve 55 is shut off. In this pumping system, the
pressure at the outlet P.sub.3 must be less than P.sub.2 which in turn
must be less than P.sub.1. The valves 54 and 55 can be controlled by the
microprocessor 16 via suitable drivers. It is to be noted that in the
pumping arrangement of FIG. 5, no positively acting pump is required, and
power requirements of the implanted unit are therefore reduced.
The rate of infusion is controlled by a microprocessor or microprocessor 16
which is part of the implantable unit 3. Throughout the specification, the
term "microcomputer" is intended to mean any miniature electronic
computing device, e.g. a microprocessor. Within the memory 15 of the
microcomputer, there is stored a program which determines the pattern of
pulsing of the pumping mechanism 8 over a period of time, as described
hereafter. The microcomputer 16 drives the pump 8 via a driver 18. The
microcomputer 16 has a built-in timer 16A which maintains continuously the
time of day in a variable location inside a random access memory 16B of
the microcomputer. Through radio frequency telemetry and transceivers 22,
25, the external controller unit 1 transmits a set of infusion rate points
to the implantable unit which will store them in the RAM 16B.
Consequently, the microcomputer 16 of the implantable unit will execute a
new profile determined by the transmitted information. During the
execution of the delivery rate, various safety factors are monitored. For
example, the state of the reservoir is checked using transducer 61 which
will be activated once the reservoir reaches 15% of its capacity. The
pumping performance of the solenoid pump 8 is monitored by circuit 14
which analyzes the shape of the voltage applied to the solenoid pump 8.
Any irregularities in the shape such as voltage level or timing to the
pulse peak are flagged to the microcomputer 16. Further, if the pumping
rate is exceeded, a maximum rate monitor in the circuit 14 shuts off the
microcomputer 16. Any lack of flow, or excessive flow, is checked by
circuit 19 which is connected to a transducer 20 attached to the wall of a
flexible tube at the output of the pump 8 prior to exit from the
implantable unit 3. Typically, the transducer 20 is a piezoceramic plate,
strain gauge or pick-up needle device which converts minor displacements
to electrical signals.
The condition of the battery 7 is checked by a low voltage detector 23, and
if a predetermined low level is reached, the state is flanged to the
microcomputer 16. Low battery level can be indicated either if the battery
7 reaches maximum impedance value or mininum operational voltage. Once
either of these states are detected, it is immediately transmitted to the
external unit 1 to warn the patient that the service life of the battery
has been reached and removal of the implantable medication unit is
required within an acceptable time frame.
The value of the patient's blood glucose concentration is obtained by
placing a sample drop of blood on a glucose test strip 2 and inserting the
test strip into a reflectance meter 34. The glucose reading is converted
into a digital value by analog-to-digital convertor 31 and passed to a
part of a microcomputer 32 in the external controller 1. The value can be
displayed on a display, such as a liquid crystal display 26 driven by LCD
driver 29, for the patient to check.
A preferred construction of the reflectance meter 34 is shown schematically
in FIG. 3. Light is emitted by a light emitting diode 41 and the light
beam is then split by beamsplitter 38 into two beams; one beam is
reflected onto a reference colour strip 39 and the other beam is reflected
onto the test strip 2. Both beams are then reflected onto a photodetector
diode 37. The intensity of the colour of the strip is related to the level
of blood glucose. Typically, a strip impregnated in peroxidase, 3.3
dimethyl 4.4 diaminobiphenyl dihydrochloride and 2.7 diaminofluorene
dihydrochloride is used. Referring to FIG. 6, when lid 53 of the
reflectance meter is open and there is no test strip 2, the only source of
light which falls upon the photodetector 37 is from the reference colour
strip 39. Once a test strip is placed in the chamber 62 and the cover 53
is closed, shutter 46 blocks the light path from the reference colour
strip 39 and the only source of light comes from the reflectance of the
test strip 2. The reflectance meter includes a battery 43, power regulator
42 and battery tester 45.
By comparing the test strip colour to the reference colour, the colour
intensity of the test strip 2 is determined and can be expressed in terms
of glucose level. Preferably, the reference colour strip 39 is chosen to
represent a colour corresponding to the middle of the blood glucose range.
The current which is generated by the photodetector diode 37 is amplified
by operational amplifier 40 and fed to an analog-to-digital converter 64
which in turn provides the information in digital form to the
microcomputer 32. Preferably, a program in the microcomputer memory checks
the level to ensure that it is not nonsensical on the basis of past
information. If it is, the controller will request repeated measurement.
Other body conditions, such as heart rate, temperature, etc. can be
monitored by a further sensor 30 the output of which is fed to the
microcomputer 32 after signal condition in circuit 65 and digital
conversion A/D converter 31.
On the basis of a mathematical model, a relationship between insulin and
glucose level is established for the patient, e.g. by his physician. The
parameters for this relationship have been previously identified during an
insulin challenge testing pulse. From the latest blood glucose
concentration reading and the mathematical model, a new infusion profile
is determined for the next time period. In addition, the controller unit 1
will recommend the time at which the next blood glucose concentration
should be measured in order to optimise the input information based on the
mathematical model.
A keypad 36 is provided to enter data and infusion parameters for the
intial setup. It can also be used to provide commands by the patient for
meal delivery requirements or in the event that the system is run as an
open loop system without blood glucose readings being used as feedback.
The communication between the implantable unit 3 and the external
controller unit 1 is in digital mode using ASCII characters. Each
character of information has a parity bit and the communication is done in
full duplex in order to reduce the effect of noise and eliminate errors.
The transmitted data is divided into nine windows of 500 microseconds. The
first window is a stand-by window followed by 7 windows of ASCII code and
an eighth window which is the parity bit. Zeroes and ones are represented
by the phase shifts of 16 kHz bursts (phase shift modulation). Once a
character is transmitted and the parity bit is verified, the receiving
unit echoes the character back to unit which then compares the transmitted
character with the received version. If the two match, transmission will
continue, otherwise the transmitted character will be repeated. In the
event that the system is exposed to an unusual source of interference and
after a predetermined number of attempts to transmit the information have
failed, the unit will abort transmission and a message will be displayed
to that effect. The above method provides secure transmission. In the
event that the transmitted character or information is nonsensical, no
action will be taken by the implanted unit. This further reduces the risk
of inadvertent programming.
The catheter 6 from the pump 8 to the body is shown in more detail in FIG.
7. The proximal end 71 of the catheter is connected to a tubing
feedthrough 66 by pulling it from a tapered fitting 69. The locking is
achieved by a bayonet type attachment in which pin 68 engages an "L"
shaped slot 77 on the proximal end 71. In the connection procedure, the
"L" shaped slot 77 is aligned with pins 68 and then pushed towards the
tapered fitting 69. The proximal end 71 is rotated clockwise and pins 68
are engaged at the blind end of the slot and pushed by the slot wall 78 in
such a manner as to provide further force in the direction of the tapered
fitting, thereby locking the proximal end 71 onto the taper fitting 69. To
disengage, the reverse procedure is adopted. In order to provide further
rigidity and seal the connection, a top cover 67, typically constructed
from an elastomer such as silicon rubber, is provided. The top of the
transmitting cover 67 has a sealing ring or lip 70 which is compressed
against the proximal end 71.
The body of the catheter is constructed from two concentric tubings. The
inner tubing 74 is made from the same material as the proximal end 71, and
preferably should by hydrophillic in order to make it compatible with the
medication, typically insulin. The inner tube 74 has a very thin wall in
order to provide flexibility. The outer tubing 73 is made from an
elastomer such as silicon rubber, or a polyurethane which is compatible
with blood as has been shown in pacemaker applications. The inner lumen of
tubing 74 is blindly terminated. However, holes 75 are drilled on the side
walls to provide outlet flow to the injected medication solution. The
distal end is covered by the tubing 73 which is stretched over the side
holes. At the outlet termination the tubing walls are collapsed at the
interface 76 as a result of the inner body pressure (P.sub.0) such as the
arterial or venous blood pressure when there is no pumping occurring.
However, when pumping takes place the pressure inside the catheter P.sub.1
is greater than P.sub.0 and the fluid flows through the side holes 75 and
between the distal end and the stretched tubing 73 to open the interface
76 and exit into the blood stream. Once the pumping stops, the pressure
inside the catheter drops below P.sub.0 and the tubing walls collapse
again, closing the interface and preventing any blood cells flowing into
the inside of the catheter.
The implantable medication infusion system of the preferred embodiment can
be operated in two modes; open loop or closed loop (with feedback). In the
closed loop (feedback) mode, the external controller 1 accepts the
feedback information from the sensor 30 or the glucose strip 2 and
provides the necessary operational commands to the implantable unit 3 by
telemetry. In this mode, there are two operational arrangements, in the
first operational arrangement the external controller acts as a master and
the implantable unit 3 operates in slave mode. The external controller
unit 1 directly activates the pumping mechanism 8 via the telemetry link
22 - 25. In this instance all the infusion profiles and timing based on
the mathematical model are calculated and executed by the external
controller unit 1, while the principal purpose of the microcomputer 16
inside the implanable unit 3 is to provide a monitoring function | | |
