Device for the Automatic Insulin or Glucose Infusion in Diabetic Subjects, Based on the Continuous Monitoring of the Patient's Glucose, Obtained Without Blood Withdrawal

The present invention relates to feedback controlled or "closed-loop" insulin pumps known also as "artificial pancreases". These devices provide a continuous glucose determination in the diabetic patient. Data is transmitted from a glucose sensor to a microprocessor unit, which controls a pump for insulin, or glucose, infusion, in order to maintain blood glucose levels within a physiological range. Glucose determination in the known closed-loop insulin pumps is achieved by two different methods. In the first, blood is continuously withdrawn from a patient's vein and reaches a glucose sensor, directly or after ultrafiltration. The principal disadvantages of this system are blood loss and/or blood clotting in the drawing tubes. The second method for a continuous glucose assay consists of the insertion of the sensor into the patient's body, usually in the subcutaneous tissue, so that blood is not withdrawn. The drawback of this system is the rapid loss of sensor reliability, probably due to fibrin and some blood cells which unavoidably reach the sensor tip. The aforedescribed disadvantages of the known closed-loop insulin pumps permit only short-term use of the devices.

In the system according to the present invention, the samples for a continuous glucose monitoring in the diabetic patient are obtained from a saline solution pumped through a hollow-fiber circuit, implanted in the patient's body. Hollow fibers are permeable to small molecules, or low molecular weight components. Thus, glucose diffuses into the fiber lumen from the surrounding body fluid. When equilibrium is reached, the pumped solution is ready for glucose assay by a suitable glucose sensor. This method avoids blood withdrawal, with the related clotting problems, and provides a long-term reliable glucose determination in diabetic patients. The present invention is of special interest for the realization of a "wearable" or implantable closed-loop insulin pump.

In order that the invention may be readily carried into effect, it will now be described with reference to the single FIGURE, which is a block diagram of an embodiment of the device of the invention.

The device of the invention consists of four principal components which are:

(a) the hollow-fiber saline solution circuit;

(b) the glucose sensor;

(c) the electronics;

(d) the infusion pumps.

This component is totally novel. A saline solution is pumped from a reservoir (3) to a glucose sensor (4) through a hollow-fiber circuit (1) by means of a piezoelectric or peristaltic pump (2). The hollow fibers are made of biocompatible material and are permeable only to small molecules or low molecular weight components. Plastic biocompatible material, such as polyacrylonitrile or polyethylene with a cut-off of 40,000, normally used in dialysis filters, may be used as the hollow fiber circuit material. Also suitable for such circuit are the materials marketed by Enka-Germany or Asahi Medical, Japan. The polyethylene may be obtained from Gambro, Sweden or Travenol, United States of America.

The hollow-fiber circuit must be implanted in the patient's body, usually in the subcutaneous tissue (15), through a short incision of the skin (14), using any local anaesthetic. The hollow fragility of the hollow fibers and the need of an adequate circuit length in a minimum space may require special arrangements of the fibers with suitable supports. The FIGURE shows a spiral-shaped hollow-fiber circuit (1), sustained by a small plastic disk (not shown in the FIGURE), implanted in the subcutaneous tissue of the abdominal wall (15). The hollow fiber number and length are chosen so as to obtain, in a short time, uniform concentration of glucose in the solution inside the fiber lumen and in the surrounding body fluid.

Biocompatible plastic tubes connect the implanted circuit with the pump (2) and with the glucose sensor (4). After the glucose assay, the solution flows towards a waste reservoir (5) or can be repumped to the hollow-fiber circuit via a circuit section indicated by broken lines in the FIGURE.

The glucose sensor (4) is preferably an enzymatic-potentiometric one, commonly used in many laboratory instruments for blood glucose determination and also in the commercially-available "artificial pancreas", such as, for instance, the Biostator marketed by Miles Laboratories.

The amplified signal coming from the glucose sensor (4) enters a microprocessor unit (6) by means of an analog to digital converter. The microprocessor (6) stores the data and, on the basis of a suitable algorithm (Albisser et al., Diabetes, May 1974), controls insulin and glucose infusion pumps (7) and (8), respectively. A display (12) of the microprocessor (6) indicates the data coming from the glucose sensor (4) and the amounts of the infused insulin and glucose. A suitable microprocessor (6) is that marketed by Motorola, Model MC1468705R3, a CMOS 8 byte MCU with timer, four-channel analog to digital converter, 2,8 Kbyte EPROM, 128 byte RAM, 4 l/O ports inside.

An insulin pump (7) and a glucose pump (8) are controlled by the microprocessor (6). Solenoid or piezoelectric micropumps can be used to infuse insulin and glucose with high precision. Insulin and glucose are taken from special reservoirs (9 and 10), respectively, and can be infused into the patient by separate biocompatible catheters or by a single dual lumen catheter (11). The administration route can be the abdominal cavity (16), the subcutaneous tissue or a peripheral vein.

The power supply for the entire system is provided by a suitable battery or batteries (13).

The device according to the present invention has been tested in animals such as, for example, rabbits and guinea pigs, and humans ranging in age from 16 to 65 years old, for a period of at least two months without any loss of sensitivity because the hollow fibers filter does not become clogged up with blood or fibrin, so that the components of blood or fibrin do not reach the sensor tip. The glucose measurements made with the device according to the present invention have been compared with glucose measurements made with conventional laboratory apparatus, specifically a Yellows Springs YSI Model 23A instrument and the values agree, showing that the device of the invention provides reliable determinations. The coefficient of correlation is 0.98 between the apparatus of the present invention and the Yellow Springs apparatus. The device of the invention may be adapted to a size of 8.times.10.times.3 cm and may be implanted into the abdominal wall of the patient. Thus, the present invention permits the avoidance of insertion of the sensor (4) directly into the subcutaneous tissue of a patient and, at the time, permits the avoidance of withdrawal of blood.

The device according to the present invention may be used not only in the case of diabetic patients for the determination of glucose, but also for the determination of many small molecular weight components in body fluids, such as sodium, potassium, calcium, and also medicines, for example, Digitalis, administered to humans in the body, so that their concentration may be monitored.