Capabilities of Next-Generation Patch Pump: Improved Precision,Instant Occlusion Detection,and Dual-Hormone Therapy

Abstract

Insulin pumps allow patients to attain better blood glucose control with more lifestyle flexibility. Their size and cost, however, limit their usefulness. Current CSII pumps are bulky, intrusive, and expensive. SFC Fluidics is addressing these problems by developing a new type of wearable patch pump based on the patented electro-chemiosmotic (ECO) microfluidic pumping technology. This nonmechanical pumping technology allows accurate and precise delivery of very small amounts of insulin and/or other drugs, including concentrated insulin. The pump engine is small and can be made inexpensively from injection molded parts, allowing its use in a disposable or semidisposable pod format. In addition, a single ECO pump engine can be used to deliver two drugs through independent pathways. Other features of SFC Fluidics’ pod include latching safety valves that prevent accidental overdosing of insulin due to pressure changes and an instantaneous occlusion sensor that can immediately detect delivery failure at the first missed dose. These features allow for the development of a series of patch pumps that will offer users the benefit of CSII therapy in a more discreet and reliable patch pump form.

There is significant evidence that people with diabetes who use continuous subcutaneous insulin infusion (CSII) have better clinical outcomes compared to those who use multiple daily injections (MDI),^1,2 however, only about 30% of people suffering from type 1 diabetes use this therapy. SFC Fluidics has developed new technology that will enable a new generation of much smaller insulin pumps. SFC is using electrical, rather than mechanical pumping, to create a range of innovative products to serve the needs of all insulin-using people with diabetes. The core electro-chemiosmotic (ECO) pumping technology delivers excellent precision, which coupled with a valve system and flow sensor, deliver a unique safety factor. Together these three technologies form a “pump engine” (Figure 1) that will be utilized for a simple patch pump, an insulin-only automated insulin delivery (AID) system, and a dual-hormone artificial pancreas (AP) system.

Figure 1.

ePump and valves.

Technical Details of ECO Pumping

Currently marketed insulin delivery pumps generally use a mechanical motion to drive a piston or a shuttle through a syringe to push the insulin into the patient. While this is a well understood and straightforward method, it does have drawbacks that limit its usefulness for delivering the small doses required by people with type 1 diabetes. The limitations of the current syringe pump technology include: ³

• precision limitations due to discrete motor movement

• inaccurate dispenses caused by stiction of the plunger

• strict design limitations due to the straight-line form requirements

• engineering constraints that prevent further miniaturization of mechanical components

The heart of SFC Fluidics patch pump system, the patented ePump® (an ECO pump), solves these problems. The ECO pump is a nonmechanical pump that is highly accurate and readily scales with delivery requirements, allowing for a more discrete product.

Fundamentally, the ECO pump is two electrochemical half-cells separated by a semipermeable membrane. Each half-cell contains an electrode, is bound on one side by a flexible, impermeable diaphragm and is filled with a nontoxic proprietary solution that supports fully reversible aqueous electrochemical reactions. Initially, each half-cell contains the same solution, and there is no movement in the pump. The application of a small voltage (≤1.5 VDC) between the two electrodes drives chemical reactions which change the osmotic pressure between the two chambers. When this happens, ions and associated solvent move from one half-cell to the other through the semipermeable membrane to equilibrate the pressure. As the fluid moves between chambers, the flexible diaphragms move to accommodate the volume change in each cell. This diaphragm movement is used to pump insulin or other drug into and out of a metering chamber that is adjacent to the flexible diaphragm. After the correct fluid volume has been pumped, the applied potential is reversed to drive the half-cells back to equilibrium. The flow rate and total volume pumped are easily controlled by controlling the rate and number of reactions that take place using established electrochemical techniques and simple electronics. The direction of the insulin flow is controlled using SFC’s latching safety valves, described later in this paper. A single stroke of this reciprocating displacement pump can be infinitely varied to deliver any amount between 0 and 1 U of U100. Larger doses are delivered using multiple strokes at a rate of 1U/min. This system is able to deliver normal, square-wave, dual-wave, or any other shape of bolus dose. The 1U/stroke limit ensures that the pump isn’t damaged during operation. A schematic diagram showing the operation of the ECO pump is shown in Figure 2.

Figure 2.

Schematic of ECO pump operation.

This type of system has several advantages over a mechanical system. First, there is no discrete stepping mechanism that limits the precision of doses that can be delivered. While existing mechanical insulin patch pumps are very good at delivering the small volumes required when using U100, they typically are limited to 0.05 U dose step sizes. For U500, this same minimum step size becomes a dose of 0.25U for existing systems. Increments of 0.05 U are fine for adults, but smaller controlled dosing increments are needed for children and are essential for migration to the use of more concentrated insulins. Other advantages stem from the construction of the ECO pump itself. For example, the liquid working material virtually eliminates engineering constraints on the shape and size of the pump. Drugs that require smaller doses, such as concentrated insulin, can be delivered using a smaller pump. The design freedom in the shape of the pump allows the pump to be tailored to fit into an organically shaped pod with consideration of the other components. A third benefit of this construction is that the pump can be made almost entirely of injection molded parts and is amenable to high-speed, automated manufacture and assembly, permitting its use in a discreet, disposable pod/patch pump type application.

Another not-so-obvious advantage of this type of reciprocating pump with potentially huge significance for diabetic therapy is that the diaphragms of both chambers move in concert as fluid is moved across the semipermeable membrane. By adding a second set of the latching safety valves, two different hormones can be independently dosed through separate fluidic pathways using a single pump engine. Each side of a dual-hormone ECO pump will have the same accuracy and precision as a single hormone ECO pump. This means that two hormones, for example insulin and glucagon, can be delivered as necessary in an AP system to either lower or raise blood sugar in response to a continuous glucose monitor (CGM) reading. Dual-hormone therapy has been shown to significantly reduce the occurrence of hypoglycemia in studies using two CSII pumps—one filled with insulin and the other with glucagon.^4-13 Although these studies have shown benefits to dual hormone therapy, the mental, physical, and financial burden of maintaining two pump systems and a CGM is too much for many people to manage, even with the prospect of reduced hypoglycemic events and better-long term outcomes. SFC Fluidics will take advantage of the dual-hormone delivery capacity of the ECO pump in meeting patient needs for comfort and discretion. The dual-hormone pod will be larger than the insulin-only AID device by only the size of the glucagon reservoir; dramatically reducing patient burden. SFC’s single-pod AP system will make dual-hormone therapy a practical treatment option for both children and adults with type 1 diabetes.

The latching safety valves are designed, as the name suggests, with safety of the patient in mind. These mechanical inlet and outlet valves are created as a set and interact with each other during operation so that they can never both be open at the same time. During the switching of the valves, both valves must close momentarily before the other can open. Once switched, the open valve physically holds the other closed so that there is never an open path from the drug reservoir to the patient. A failure of the pump or external pressure change such as during an airplane flight will not cause an overdosing of the insulin to the patient. The outlet valve to the patient is always closed when the pump is not actively dispensing insulin to the patient. When pumping is initiated, both valves are closed and then the outlet valve is open. The pump delivers the prescribed dose and then the valves close again before the valve to the drug reservoir is open. The pump then returns to equilibrium by drawing the same amount of drug from the reservoir. In this way, failure of the pump cannot cause an overdelivery of insulin to the patient.

The final piece of technology SFC has incorporated into the pod, adding yet another layer of safety and reliability to the device, is the instantaneous occlusion sensor. A main failure point in continuous insulin infusion is silent occlusions.^14-16 While this is primarily an infusion set/insertion issue, existing occlusion sensors are unable to reliably detect the occlusion in a timely manner. Too often, occlusions are “silent” and detected when correction boluses are required to remedy a hyperglycemic condition. A key benefit of SFC’s pod is the ability to confirm drug flow in real-time. Instantaneous confirmation of individual basal dispenses may allow for detection of infusion set faults or other occlusions within minutes. The flow confirmation sensor sits in line with the drug delivery path between the valve and cannula tip and consists of a series of electrodes. When a potential is applied, the fluid supports a very small (nanoamperes) electrical current. This characteristic current depends on fluid composition such as ionic strength and viscosity. During pumping, the sensor confirms fluid flow by measuring an increase in current due to convection augmenting movement of charge carriers over diffusion alone. In addition to being fast and accurate, SFC’s occlusion sensor is also quite small with a sensing length of 1.5 mm and a diameter of 0.5 mm. The sensors are fabricated by mass manufacturable methods common in the electronics industry and can be made at a size and cost suitable for disposable use. The power requirements are very low as well, requiring a few microamperes during fluid flow but with the ability to be switched off completely between dispenses. Finally, the processing power needed to confirm flow is low as well, and easily within the capabilities of a pod control system. Rapid detection of dispense failure is key to diagnosing occlusions, whether from kinked cannulas or other possible faults. Accurate occlusion detection holds the promise of reducing time in hyperglycemia.

Figure 3 shows one potential design layout of the components that would be used for the Bluetooth®-enabled, 3-day use, fully disposable insulin-only CSII pod.

Figure 3.

Rendition of insulin delivery pod. The pod as designed is 51 mm × 55 mm × 13 mm.

Performance Details

ECO pump and valves

During the development of the ECO pump technology, several key aspects of the technology were proven before it could be considered as a technology capable of delivering life-saving drugs in a miniaturized embodiment. One of the early questions was how this technology would be affected by any backpressure in the system. Many nonmechanical pumps are not capable of pumping reliably against backpressure. Electroosmotic pumps that use surface charge of a porous frit to generate fluid movement are significantly affected by small changes in backpressure. Conversely, the ECO pump has been shown to operate well against backpressure and was able to generate enormous amounts of pressure when pumping into a closed chamber. A well-fortified ECO pump was used to generate a pressure of 23 atm (300 psi) in a closed chamber (see Figure 4). ¹⁷ This capability assures reliable operation during subcutaneous delivery of drugs.

Figure 4.

An ECO pump is used to generate 23 atm of pressure in a closed chamber. The pump was operated at 20 mA reaction current to generate the pressure. After a brief rest period, the reactions were reversed at −20 mA to release the pressure.

In addition, the accuracy of the pump had to be characterized over a wide range of potential operating environments. Unlike a motor driven pump, there is no mechanical displacement that can be measured to determine how far a shuttle or plunger has moved. Instead of counting the number of steps of a motor, ECO pump calibration is based on the number of reactions that take place inside the pump. While this is an easy measurement to make, there are many factors that can affect the result. It was shown that different solutions and solvents and even different ionic concentrations affect the amount of fluid that moves across the semipermeable membrane per unit charge.^18,19 It was also shown that for a given solution, the pumping efficiency, measured as volume of fluid delivered per number of reactions, was constant over the broad temperature range applicable to drug delivery (5-55°C), though the pump works faster at higher temperatures (see Figure 5). The ECO pump can be tailored to work at a certain efficiency and nominal flow rate while maintaining dosing accuracy over a broad temperature range.

Figure 5.

Shows the efficiency of an ECO pump remains constant at temperatures ranging from 5-55°C while the flow rate increases linearly with temperature.

Once these technical characteristics were understood, the ECO pump technology was optimized for use in a wearable drug delivery device for delivery of insulin to people who suffer from type 1 and type 2 diabetes. The flow rates and energy requirements could be met with a pump with chambers that were only 12.5 mm in diameter and 3 mm high. Once this pump was designed and built, IEC testing was begun.

The International Electrotechnical Commission (IEC) has defined the standard for measuring and presenting the error of dispenses for ambulatory drug infusion pumps in their IEC 60601-2-24 document. ²⁰ In this procedure, a pump is used to pump a dose of water onto a balance repeatedly, and the measured change in mass is used to calculate the volume of liquid that was dispensed. Pump accuracy and precision are clearly presented in a “Trumpet Curve.” This chart conveniently displays the maximum amount that the pump over or under dispensed over any specified time interval during the testing. As the time interval is increased, the values approach the overall average value, giving a trumpet shape. The ECO pump and valves have been rigorously tested using an IEC 60601-2-24 compliant test setup. The results of these tests are shown in Figure 6. The figure shows the trumpet curve for a basal delivery routine of 0.5 U/h dispensed as 0.05 U every 6 minutes over a total of 48 hours.

Figure 6.

Trumpet curve for 48-hour basal testing of ECO pump and valves. 48-hour total error is 0%.

In a separate experiment, an ECO pump was coupled with two sets of latching safety valves, and two IEC 60601-2-24 compliant test apparatus were used to measure the ability of the ECO pump to independently deliver doses using both sides of the pump. After initial verification that the system works, the dual-hormone pump prototype was used to replicate the doses given to a patient in a published dual-hormone AP trial study (Patient 303). ²¹ One side of the pump dosed the insulin protocol and the other delivered the required glucagon. In the published dual-hormone study, an algorithm was used to calculate a dose every 5 minutes using readings from a CGM (sometimes the dose was 0 mg). The dispenses ranged from 0-20 µL (0-2 U) of insulin and 0-6 µL (0-30 µg) for glucagon. The total error for insulin was −2.8% over the 48-hour period. For glucagon the dosing error was +1.8%. Each side of the two-sided ECO pump prototype demonstrated precision comparable to that of the single-sided ECO pump and existing insulin only pumps, as shown in the trumpet curves in Figure 7.

Figure 7.

Shows the trumpet curves from 48-hour dual hormone AP dosing schedule onto dual IEC 60601-2-24 compliant test setups. The trumpet curves for insulin (black dots) and glucagon (green dashes) were calculated separately.

Occlusion Sensor Test Results

Commercially available rapid acting insulins give similar response from the occlusion sensor due to their similar fluid composition (Figure 8). The graphs in Figure 8 are of solutions mixed based on formulations available from the package insert for the three-predominant rapid acting insulin analogs on the market. The graph for each solution shows four dispenses of 1 U (10 µL) given over a 5-minute time span. Apidra® carrier solution is shown in green while Humalog® and Novolog® are depicted with red and blue respectively. Each increase in signal corresponds to a dispense of 1 U through the occlusion sensor at a flow rate of 20 µL/min for 30 seconds. Data were taken for each formulation separately and overlaid to create the figure. For each dispense there is a rapid increase in the current from the sensor when flow is initiated and a corresponding quick decrease when flow is stopped.

Figure 8.

Carrier solution for three rapid acting insulin analogs show similar response during pumping of 1U equivalent volume.

The current measured by the sensor during pumping is significantly higher than when the solution is at rest, with signal amplitude indicative of flow rate (Figure 9). The data in Figure 9 show current response at various rates from 5-20 µL/min, indicating the sensor can be used to identify partial occlusions as well. In this figure, dispenses were fixed to 30 seconds, so 10 µL/min and 5 µL/min dispenses are equivalent to 0.5U and 0.25U, respectively. In case of a partial occlusion the pump would dispense the correct amount, but the low flow rate would occur over a long-time period. By measuring both the flow rate as well as duration of flow, the sensor can confirm dosage dispensed. The occlusion sensor responds quickly to initiation of flow and can sense occlusion of volumes as small as 0.05 U of U100 rapid acting insulin, allowing confirmation of individual basal dispenses.

Figure 9.

Graph of sensor response at different flow rates relevant for SFC pod. Signal amplitude is indicative of pumping speed.

Conclusion

SFC Fluidics’ microfluidic technologies represent a significant step forward in the development of CSII treatment of diabetes, allowing for safe, accurate continuous subcutaneous insulin injection in a reduced footprint for type 1 and type 2 diabetes and greatly increasing the speed at which occlusions are detected.