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Journal of Diabetes Science and Technology logoLink to Journal of Diabetes Science and Technology
. 2019 Oct 14;13(6):1017–1025. doi: 10.1177/1932296819881456

The Bio-inspired Artificial Pancreas for Type 1 Diabetes Control in the Home: System Architecture and Preliminary Results

Pau Herrero 1,✉, Mohamed El-Sharkawy 1, John Daniels 1, Narvada Jugnee 2, Chukwuma N Uduku 2, Monika Reddy 2, Nick Oliver 2, Pantelis Georgiou 1
PMCID: PMC6835194  PMID: 31608656

Abstract

Background:

Artificial pancreas (AP) technology has been proven to improve glucose and patient-centered outcomes for people with type 1 diabetes (T1D). Several approaches to implement the AP have been described, clinically evaluated, and in one case, commercialized. However, none of these approaches has shown a clear superiority with respect to others. In addition, several challenges still need to be solved before achieving a fully automated AP that fulfills the users’ expectations. We have introduced the Bio-inspired Artificial Pancreas (BiAP), a hybrid adaptive closed-loop control system based on beta-cell physiology and implemented directly in hardware to provide an embedded low-power solution in a dedicated handheld device. In coordination with the closed-loop controller, the BiAP system incorporates a novel adaptive bolus calculator which aims at improving postprandial glycemic control. This paper focuses on the latest developments of the BiAP system for its utilization in the home environment.

Methods:

The hardware and software architectures of the BiAP system designed to be used in the home environment are described. Then, the clinical trial design proposed to evaluate the BiAP system in an ambulatory setting is introduced. Finally, preliminary results corresponding to two participants enrolled in the trial are presented.

Results:

Apart from minor technical issues, mainly due to wireless communications between devices, the BiAP system performed well (~88% of the time in closed-loop) during the clinical trials conducted so far.

Preliminary results show that the BiAP system might achieve comparable glycemic outcomes to the existing AP systems (~73% time in target range 70-180 mg/dL).

Conclusion:

The BiAP system is a viable platform to conduct ambulatory clinical trials and a potential solution for people with T1D to control their glucose control in a home environment.

Keywords: type 1 diabetes, automatic insulin delivery, artificial pancreas, bio-inspired technology, low-power electronics

Introduction

In the last two decades, technological progress in the field of diabetes management, especially in continuous glucose monitoring (CGM),1 has enabled the development of automated insulin delivery systems, the so-called artificial pancreas (AP). The most common configuration of an AP consists of a CGM sensor and a subcutaneous infusion pump that delivers insulin at a rate decided by a computer program (control algorithm).2,3

Clinical studies have shown that an AP can achieve greater time in glucose target than standard treatment in which a person makes insulin dosing decisions.4 The commercialization of the first AP, the Medtronic 670G SmartGuard (Medtronic, CA, United States),5 occurred in 2018 and multiple further prototypes have been assessed.6 At the time of writing this paper, 13 companies involved in AP programs were identified: Medtronic, Roche, Dexcom, Insulet, Bigfoot, Tandem, Kaleido, TypeZero, Inreda, Beta Bionics, Cellnovo, Medtrum, Lilly, and Diabeloop.7

Many control algorithms have been described and clinically evaluated, including Model Predictive Control,8-12 Proportional Derivative Integral,13,14 Fuzzy Logic,15 and Bio-inspired.16 However, none of these controllers have yet shown a clear superiority when compared to the others in a clinical setting.4,17

The current limitations of subcutaneous insulin pharmacokinetics have limited the realization of a fully automated AP system able to control glucose levels at meal time. A practical solution to this problem is the hybrid AP system in which mealtime insulin delivery is manually assisted by announcing the meals.18

Physical exercise, together with meals, is probably the biggest challenge an AP has to face.19 When dealing with aerobic exercise, AP systems have to avoid hypoglycemia during activity, while the previously administered insulin remains active. There is already clinical evidence that by announcing exercise, an AP can better cope with such perturbation by reducing the exercise-induced hypoglycemia.20 Another possible solution to address this challenge is the incorporation of glucagon delivery as counter-regulatory action to insulin in a dual-hormone AP.21 Although a dual-hormone AP has a potential benefit over its insulin-only counterpart, its development and commercialization has been delayed by the lack of a commercial stable glucagon solution.22

Another challenge AP systems face is the significant interday variability in insulin requirements that people with diabetes are subject to.23 A solution to this problem is the inclusion of adaptive control mechanisms which automatically adjust the controller setting according to the insulin requirements.24,25

In this paper, we provide an overview of the Bio-inspired Artificial Pancreas (BiAP), a hybrid adaptive closed-loop control system based on a model of the beta-cell insulin secretion physiology which has been implemented in a dedicated low-power handheld device.

The first generation of the Bio-inspired Artificial Pancreas (BiAP Gen 1) was created in 2012. It consisted of a custom-made microcontroller-based handheld unit connected to a Medtronic Enlite sensor (Medtronic Diabetes, Northridge, CA, United States) and an Accu-Chek Spirit Combo insulin pump (Roche, Basel, Switzerland) (Figure 1).26 The BiAP Gen 1 closed-loop control algorithm, implemented in the microcontroller, utilized a subcellular model of insulin secretion obtained from physiological data. This subcellular model of insulin release is able to replicate the majority of the experimental data, including biphasic insulin secretion, staircase modulation of insulin secretion, the potentiation effect of glucose, and kiss-and-run secretion by insulin granules.27 Such model was then augmented by an insulin feedback term28 and a predictive low-glucose suspend safety module to compensate for the mismatch between endogenous insulin secretion and subcutaneous insulin delivery.

Figure 1.

Figure 1.

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The first generation of the Bio-inspired Artificial Pancreas composed of a handheld unit which communicated to a Medtronic Enlite Sensor and an Accu-Chek Spirit Combo insulin pump.

A bihormonal version of the BiAP Gen 1 system, which includes a proportional derivative controller for glucagon delivery, was also developed and evaluated.29

The first generation of the Bio-inspired Artificial Pancreas was clinically tested in participants with type 1 diabetes (T1D) during fasting conditions, overnight, and following a standard meal (breakfast) challenge, and the data showed good glycemic control with minimal hypo- or hyperglycemic excursions.30 Following the feasibility studies, a 24-hour randomized control clinical trial demonstrated that the BiAP Gen 1 system significantly reduces hypoglycemia compared to standard insulin pump therapy.31 In a substudy, we showed that participants using BiAP Gen 1 remained safe in the event that a meal is unannounced or the carbohydrate content is underestimated.31

The BiAP Gen 1 system was also evaluated in standard exercise studies with insulin-only closed-loop control, insulin and glucagon closed-loop control, and standard open-loop insulin pump therapy. These demonstrated that the closed-loop controller is able to manage the challenge of prolonged aerobic exercise and suggested that the addition of glucagon does not impact on the risk of hypoglycemia and hyperglycemia with physical activity, immediately after physical activity or up to 16 hours after.32,33

In this paper, we present the latest developments of the BiAP system for its utilization in the home environment. Finally, the design of the ambulatory clinical trial and some preliminary results are presented.

Methods

After proving that the BiAP system was safe and effective under different real-life scenarios (unannounced meals and exercise), the next logical step is to evaluate the system in an ambulatory environment. For this purpose, both the BiAP system hardware and software have been upgraded in order to improve the portability, usability, and performance of system.

Handheld Unit

The core hardware component of the second generation of the Bio-inspired Artificial Pancreas (BiAP Gen 2) is the custom-made handheld unit (9×5 cm) shown in Figure 2. The unit consists of a custom-designed printed circuit board (PCB) contained within a 3D-printed box that has two main components, an embedded microchip that runs the bio-inspired closed-loop control algorithm (see the section “Closed-Loop Control Algorithm”), and a Nordic nRF52832 chip which handles the Bluetooth communication with the insulin pump, the glucose sensor, and a smartphone. The unit also includes an SD memory card in which the user settings are uploaded, and all input and output data are stored. A micro-USB port is available for battery charging and data transition. An OLED screen and three buttons allow the user to interface with the unit. User interaction includes starting and stopping the unit; pairing the peripheral Bluetooth devices; basic data visualization, such as CGM measurement, glucose trend, delivered insulin, connectivity status, and historical glucose and insulin data. Users can choose to switch from closed-loop control model to open-loop model (ie, standard therapy) and vice versa, at their will, by selecting the corresponding option in the BiAP unit menu.

Figure 2.

Figure 2.

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The second generation of the Bio-inspired Artificial Pancreas architecture and information flow.

The PCB also includes a buzzer which is used to alert the user about malfunctioning of the system (eg, loss of wireless connectivity) and hypoglycemia. In the event of a device disconnection, the system automatically tries to reconnect the lost device for a predefined number of times, and if unsuccessful, then an audible alarm is triggered.

Further details about the BiAP hardware architecture, its power consumption, and hardware-in-the loop testing have been published.34

The BiAP Gen 2 system interfaces with the Tandem t:slim AP (Tandem Diabetes Care, San Diego, CA, United States) insulin pump and the Dexcom G6 glucose sensor (Dexcom, San Diego, CA, United States) continuous glucose sensor.

The BiAP unit receives a glucose value from the Dexcom G6 transmitter every five minutes, calculates an insulin dose, which is subsequently sent to the insulin pump for delivery. In addition, the BiAP unit connects to a smartphone running Apple iOS (Apple, Cupertino, CA, United States) and a dedicated app implementing an adaptive bolus calculator (ABC) used to calculate the meal insulin dose (see the section “Adaptive Meal Bolus Calculator”). Finally, insulin, CGM, and meal data are uploaded through the phone to a MySQL database hosted in the cloud (Amazon Web Services) for remote monitoring purposes. The reason for including a smartphone is because the employed ABC requires sending data to a server for the clinical supervision of its automatic adaptations. However, once the system has been validated, the adaptations can run locally on the BiAP unit and the phone can be eliminated. Figure 2 shows the BiAP Gen 2 architecture and the information flow between different components.

Closed-Loop Control Algorithm

The closed-loop glucose controller implemented in the microcontroller of BiAP Gen 2 has been previously described in Herrero et al.35 In this updated version of the controller, the pancreatic insulin secretion model used in BiAP Gen 116 has been replaced by the most recent model,36 with improved performance in simulation studies as well as reduced complexity which significantly speeds up the computations in the microcontroller and consequently saves power. In particular, the computation time has been reduced from 60 seconds to less than 10 seconds.

Appendix A provides a mathematical proof showing that the employed pancreatic insulin secretion model is equivalent to a proportional derivative controller with two low-pass filters. The low-pass filters can be thought of as human physiology smoothing out any abrupt transients in glucose, an inherent mechanism to remove noise from sensed glucose and provide smoother control. Finally, the tuning of the controller has been simplified so that only the insulin sensitivity factor (correction factor) and the user’s basal insulin profile are needed.

Adaptive Meal Bolus Calculator

The second generation of the Bio-inspired Artificial Pancreas is a hybrid AP system which implements a novel ABC which operates in coordination with the closed-loop controller.35

There is significant evidence that good basal control (eg, overnight control) is relatively easy to achieve independently to the employed control strategy.15,30 Therefore, the main improvement in glycemic control can be achieved during the postprandial period, and potentially during and after exercise. Therefore, the inclusion of an ABC that works in companionship with the closed-loop control law can potentially outperform the existing hybrid closed-loop systems.35

The ABC is implemented on an iOS app which also acts as a graphical user interface for the AP system. Screenshots of the app’s graphical user interface are shown in Figure 3. Continuous glucose monitoring data are automatically transmitted from the BiAP unit to the phone. These readings can be overwritten by the user if considered inaccurate. Connectivity between the BiAP unit and the phone is indicated by a green indicator located the top-right corner of the screen (Figure 3(a)). In order to receive a meal insulin bolus recommendation, the user estimates the mealtime carbohydrate content and, if any, the planned physical exercise (none, moderate, and intense). The suggested insulin dose can be modified by the user in the recommendation screen by using the +/− buttons (Figure 3(b)). Details about the calculation of the insulin dose recommendation can be obtained by clicking at the “View Details” button. Once accepted, the meal insulin dose is automatically transmitted to the BiAP unit for delivery. Insulin-on-board used by the ABC is obtained from the pump via the BiAP unit. The iPhone app can also be used to visualize glucose and insulin historical data and a log of all the past entries.

Figure 3.

Figure 3.

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Bio-inspired Artificial Pancreas iPhone app graphical user interface: (a) main screen for data input and (b) recommendation screen.

Exercise Announcement

The second generation of the Bio-inspired Artificial Pancreas exercise announcement strategy is based on knowledge acquired from the previous in-clinic closed-loop trials involving exercise30,31 and the existing clinical guidelines.37 In particular, at mealtime, if users plan to exercise after the meal, they can activate the exercise function available in the iPhone app. This will automatically reduce the recommended meal bolus by 30%. Then, before or during exercise, the user can additionally press the exercise button on the app which will reduce the insulin dose delivered by the closed-loop controller by 50% for 90 minutes. The BiAP will then beep and display an icon of an individual running on the main GUI screen to indicate that system is in the exercise mode. The exercise mode can be stopped at any time within the app.

It is worth noting that glucose levels were not accounted for within the employed exercise announcement strategy, the reason being that, in the previous clinical trials, we observed that actual blood glucose levels can drop relatively quickly after the initiation of exercise (<30 minutes), while CGM measurements are significantly lagging behind. Hence, adjusting insulin delivery based on glucose levels at exercise time might not always be a good strategy. Although the employed strategy for minimizing exercise-induced hypoglycemia might be suboptimal for very elevated blood glucose levels (eg, >300 mg/dL), and a more elaborated strategy might be required, we opted for the more conservative approach. In the event of significant hyperglycemia, participants were advised to check their blood ketones and take the corresponding correction actions to normalize glycemia (eg, small correction bolus) before engaging with exercise.

Safety Layer

Safety is paramount in any insulin delivery system, hence the importance of a safety layer within an AP system.38 In BiAP Gen 2, individualized constraints based on user-specific parameters (eg, basal insulin) are applied to the insulin calculated by the closed-loop controller. In particular, the closed-loop controller is not allowed to deliver more than six times the basal insulin delivery within an hour. The iPhone ABC app has in-built constraints that limit the amount of carbohydrate that can be manually inputted. Hypoglycemia prevention strategies including basal insulin infusion reduction and suspension are employed for forecasted glucose concentrations below the predefined thresholds. Glucose forecasting is carried out by means of a linear regression algorithm which accounts for the current glucose levels and glucose rate of change. Glucose forecasting horizon is fixed to 20 minutes. A predictive low-blood insulin suspension algorithm reduces the basal insulin delivery by 50% if the forecasted glucose value falls below a predefined threshold (80 mg/dL) and suspends the basal insulin delivery if it falls below a second lower predefined threshold (70 mg/dL). To prevent rebound hyperglycemia, the basal insulin suspension is limited to 90 minutes, after which time the insulin delivery is resumed to 50% for 30 minutes, and after this period, total suspension is activated again if the hypoglycemic condition is satisfied. It is worth noting that the closed-loop control algorithm does not deliver additional insulin, while the low-blood insulin suspension algorithm is acting on the basal insulin delivery.39

An alarm system for wireless communication disconnection between devices is in place. To reduce alarm fatigue, alarms due to communication problems are not triggered until 20 minutes of disconnection have elapsed. During this time, the system tries to reconnect. In addition to the glucose alarms provided by the Dexcom G6 mobile app, the BiAP unit has an additional hypoglycemia alarm.

In the case of sensor or pump disconnection, insulin infusion reverts to a safe basal rate (70% of preprogrammed rates). The reason for not reverting to 100% of the basal insulin is to minimize the risk of a potential nocturnal hypoglycemic event, since the low-glucose suspension mechanism is disabled during disconnection time.

Real-time remote monitoring of CGM, insulin, and meal data is available through a web browser (Amazon Web Services). Finally, automatic alarms to the expert team, sent via email, are available.

Clinical Trial Design

The main objectives of the research study are to evaluate the safety, efficacy, and cost-effectiveness of a BiAP Gen 2 with, and without, the addition of the ABC compared to gold-standard sensor-augmented pump therapy. Adaptations of the ABC are performed offline every two weeks.

The study design consists of a three-way crossover open label randomized controlled trial. The total duration of the study is 24 weeks with two weeks run-in period, six weeks per way, and wash-out periods of two weeks. Figure 4 shows a graphical representation of the proposed study design. The study population are 20 adults with T1D. Inclusion criteria were adults over 18 years of age, T1D confirmed on the basis of clinical features and a fasting c-peptide <200 pmol/L; T1D for greater than one year; continuous subcutaneous insulin infusion for greater than six months; HbA1c <10% (86 mmol/mol); and compliance with sensor augmented pump therapy during run-in period. Exclusion criteria were more than one episode of severe hypoglycemia (defined as hypoglycemia requiring third party assistance) in the preceding year; hypoglycemia unawareness; pregnant or planning pregnancy; breastfeeding; enrolled in other clinical trials; have active malignancy or under investigation for malignancy; severe visual impairment; reduced manual dexterity; ischemic heart disease; anti-anginal medications (eg, glyceryl trinitrate); unable to participate due to other factors, as assessed by the clinical investigator.

Figure 4.

Figure 4.

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Clinical trial design for evaluation of the second generation of the Bio-inspired Artificial Pancreas in the home environment.

The primary outcome from the studies is percentage time spent with a glucose concentration in the target range 3.9 to 10.0 mmol/L. This outcome incorporates safety as it ensures participants do not have low or high glucose excursions and is the principal measure of efficacy for closed-loop insulin delivery systems in the scientific literature. Secondary outcomes include percentage time spent in euglycemia (3.9-7.8 mmol/L), percentage time spent in hypoglycemia (<3 and <3.9 mmol/L), percentage time spent in hyperglycemia (>10 mmol/L), mean venous blood and sensor glucose, glycemic variability as measured by standard metrics, glycemic risk as measured by low blood glucose index and high blood glucose index, closed-loop error grid analysis, and glucose area under the curve. All measures have been previously published and validated.40 Quality of life, treatment satisfaction, and device acceptability outcomes will be measured using mixed methods (questionnaires and semistructured interviews).

Results

At the time of writing this report, two participants, one allocated to the BiAP+Standard bolus arm (Participant #1) and the other to the BiAP+ABC arm (Participant #2), had been in the trial for a duration of approximately two weeks (Participant #1: 11 days; Participant #2: 16 days). Since adaptation of the ABC is scheduled every two weeks, there was no time to perform any adaptation on the participant on the BiAP+ABC arm.

Preliminary glycemic results corresponding to Participant #1 and Participant #2 are reported in Table 1. Glucose metrics are analyzed per day and presented as median ± interquartile range (IQR). In particular, we report percentage time in glucose target range 70 to 180 mg/dL; percentage time below 54 mg/dL; percentage time below 70 mg/dL; and percentage time above 180 mg/dL. Figure 5 shows the CGM trace and insulin data for two selected days corresponding to Participants 1 and 2. Table 2 reports the average correction boluses administered per day and the average exercise announcements per day for each participant.

Table 1.

Glycemic Outcomes Corresponding to Two Enrolled Participants Expressed as Median ± IQR.

Participant Glucose, mg/dL %T in 70-180 mg/dL %T < 54 mg/dL %T < 70 mg/dL %T > 180 mg/dL
#1 154 ± [141, 168] 70 ± [57, 83] 0.0 ± [0.0, 0.0] 1.6 ± [0.0, 1.6] 28 ± [16, 41]
#2 136 ± [122, 150] 77 ± [67, 88] 0.0 ± [0.0, 0.0] 5.1 ± [3.0, 7.3] 22 ± [4, 26]
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Figure 5.

Figure 5.

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Continuous glucose monitoring and insulin data for a selected day corresponding to Participant 1 (a) and Participant 2 (b). In the lower graph, blue bars correspond to microboluses delivered by the Bio-inspired Artificial Pancreas closed-loop controller, while green and red bars represent meal boluses and correction boluses, respectively. Cyan bar indicates the time the exercise was announced.

Table 2.

Average Correction Boluses Administered Per Day and Average Exercise Announcements Per Day for Each of the Two Participants.

Participant Correction boluses per day Exercise announcements per day
#1 1.3 0
#2 2.7 0.3
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Regarding the device connectivity and safety measures, Table 3 reports the percentage time the CGM was connected to the BiAP; total number of pump disconnections; percentage time in closed-loop mode; the number of hypoglycemia alarms; and the percentage of time the low-blood insulin suspension algorithm was active (ie, partial suspension and total suspension).

Table 3.

Device Connectivity Metrics, Hypoglycemic Alarms, and Low-Blood Insulin Suspension Time.

Participant % Time CGM connected Total number of pump disconnections per day % Time in closed loop No. of hypo alarms per day % Time in partial suspension % Time in total suspension
#1 97.3 0.3 90.2 0.6 8.3 6.7
#2 99.3 0.5 86 0.7 13.0 6.4
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Abbreviation: CGM, continuous glucose monitoring.

There were no reported adverse events or serious adverse events during the study to date.

Discussion

Despite the limited amount of clinical data, preliminary results from the first two participants show that BiAP Gen 2 achieves comparable glycemic outcomes to the existing AP systems in comparable conditions.5

Concerning the device connectivity, the communication with the sensor was reliable (97.3% and 99.3% of the time connected). On the other hand, some disconnections were experienced with the communication to the pump. The Tandem t:slim insulin pump modified for AP clinical trials has a known issue arising from the Bluetooth chip which randomly disconnects and does not reconnect unless the Bluetooth on the pump is toggled off and on. This was also seen by other groups using this pump.41,42 The percentage time in closed-loop mode was comparable to the one achieved in other clinical trials.42

When looking at the individual results, Participant 2 is more prone to administering correction boluses and also does some physical exercise. In addition, Participant 2 spent less time in the closed-loop mode. This might explain the slightly higher percentage of time spent in mild hypoglycemia.

Regarding the usability of the system, carrying four devices (handled unit, phone, pump, and CGM) is not optimal, hence the plan for future generations of the system is to eliminate some of the devices. For instance, as a result of its low computational requirements and its proven implementation on an embedded platform, the employed control algorithm can be easily integrated in the microcontroller of any insulin pump. Similarly, the ABC could also be integrated within a pump like Tandem t:slim, which offers a graphical user interface sufficient for the required interaction.

Conclusion

The BiAP Gen 2 system is a viable AP platform to conduct ambulatory clinical trials and a potentially solution for people with T1D to achieve better glucose control in a home environment. However, additional clinical results are needed for validation.

Supplemental Material

Appendix_A – Supplemental material for The Bio-inspired Artificial Pancreas for Type 1 Diabetes Control in the Home: System Architecture and Preliminary Results
Click here for additional data file. (147.5KB, pdf)

Supplemental material, Appendix_A for The Bio-inspired Artificial Pancreas for Type 1 Diabetes Control in the Home: System Architecture and Preliminary Results by Pau Herrero, Mohamed El-Sharkawy, John Daniels, Narvada Jugnee, Chukwuma N. Uduku, Monika Reddy, Nick Oliver and Pantelis Georgiou in Journal of Diabetes Science and Technology

Footnotes

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project has received funding from the Wellcome Trust (100921/Z/13/Z).

Supplemental Material: Supplemental material for this article is available online.

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Supplementary Materials

Appendix_A – Supplemental material for The Bio-inspired Artificial Pancreas for Type 1 Diabetes Control in the Home: System Architecture and Preliminary Results
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Supplemental material, Appendix_A for The Bio-inspired Artificial Pancreas for Type 1 Diabetes Control in the Home: System Architecture and Preliminary Results by Pau Herrero, Mohamed El-Sharkawy, John Daniels, Narvada Jugnee, Chukwuma N. Uduku, Monika Reddy, Nick Oliver and Pantelis Georgiou in Journal of Diabetes Science and Technology

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