Wearable Artificial Pancreas Research Articles

Emerging Technologies in Endocrine Drug Delivery: Innovations for Improved Patient Care.

Recent advancements in drug delivery systems for endocrine disorders have significantly improved patient outcomes by addressing the limitations of traditional methods such as oral tablets and injections. These innovations include non-invasive alternatives like inhaled insulin, which provides rapid absorption and better patient compliance, and robotic pills that deliver drugs directly to specific gastrointestinal sites, enhancing absorption and reducing side effects. Wearable artificial pancreas systems have revolutionized diabetes management by integrating continuous glucose monitoring with insulin pumps to automate blood glucose control. These systems demonstrate superior glycemic control and reduce hypoglycemic events. Additionally, smart insulin pens enhance diabetes care through dose tracking and real-time data sharing, improving accuracy and adherence. Microneedle patches offer a minimally invasive method for transdermal drug delivery, effectively administering hormones and therapeutic peptides without the pain and inconvenience of injections. These patches dissolve after use, eliminating biohazardous waste. Implantable devices provide long-term, controlled release of medications, significantly improving adherence and glycemic control of patients with diabetes. Hydrogels also offer new drug delivery options. This review examines these technologies' clinical efficacy, safety, advantages, and limitations, highlighting their potential to transform endocrine disorder management. Integrating advanced delivery systems marks a significant step towards personalized medicine, tailoring treatments to individual patient needs for better health outcomes.

An intelligent wearable artificial pancreas patch based on a microtube glucose sensor and an ultrasonic insulin pump

In order to improve the living standards of diabetes patients and reduce the negative health effects of this disease, the medical community has been actively searching for more effective treatments. In recent years, an artificial pancreas has emerged as an important approach to managing diabetes. Despite these recent advances, meeting the requirements for miniaturized size, accurate sensing and large-volume pumping capability remains a great challenge. Here, we present a novel miniaturized artificial pancreas based on a long microtube sensor integrated with an ultrasonic pump. Our device meets the requirements of achieving both accurate sensing and high pumping capacity. The artificial pancreas is constructed based on a long microtube that is low cost, painless and simple to operate, where the exterior of the microtube is fabricated as a glucose sensor for detecting diabetes and the interior of the microtube is used as a channel for delivering insulin through an ultrasonic pump. This work successfully achieved closed-loop control of blood glucose and treatment of diabetes in rats. It is expected that this work can open up new methodologies for the development of microsystems, and advance the management approach for diabetes patients.

An event-triggered active disturbance rejection approach to dual-hormonal artificial pancreas control

The home-use of a wearable artificial pancreas (AP) system requires an efficient and robust control algorithm. In this work, we propose a novel solution through an adaptive disturbance rejection approach. The controller features an observer that estimates the effect of improper clinical parameters and a feedback control law that builds on and compensates the estimated effect. Event-triggered data scheduling is designed for the state observer and the insulin-on-board estimate, to enable predictive control action for ascending and descending glucose traces. Besides, an event-triggered switching strategy is proposed to deliver insulin and glucagon separately. Glucose- and velocity-dependent parameter adaptation for the feedback control law are further introduced for each hormone infusion to address the asymmetric risks of hyperglycemia and hypoglycemia. The effectiveness and robustness of the controller are evaluated using the 10-adult cohort of the FDA-accepted UVA/Padova T1DM simulator. For scenarios with nominal basal rates and meal boluses, the proposed controller achieves satisfactory performance in terms of mean glucose and percent time in [70, 180] mg/dL without increasing the risk of hypoglycemia. The controller also behaves properly and safely with satisfactory performance for scenarios of moderate meal-bolus and basal rate mismatches. The results indicate the feasibility of achieving robust glucose regulation through an adaptive disturbance compensation approach for dual-hormonal AP systems.

Clinic-on-a-Needle Array toward Future Minimally Invasive Wearable Artificial Pancreas Applications.

In order to reduce medical facility overload due to the rise of the elderly population, modern lifestyle diseases, or pandemics, the medical industry is currently developing point-of-care and home medical device systems. Diabetes is an incurable and lifetime disease, accountable for a significant mortality and socio-economic public health burden. Thus, tight glucose control in diabetic patients, which can prevent the onset of its late complications, is of enormous importance. Despite recent advances, the current best achievable management of glucose control is still inadequate, due to several key limitations in the system components, mainly related to the reliability of sensing components, both temporally and chemically, and the integration of sensing and delivery components in a single wearable platform, which is yet to be achieved. Thus, advanced closed-loop artificial pancreas systems able to modulate insulin delivery according to the measured sensor glucose levels, independently of patient supervision, represent a key requirement of development efforts. Here, we demonstrate a minimally invasive, transdermal, multiplex, and versatile continuous metabolites monitoring system in the subcutaneous interstitial fluid space based on a chemically modified SiNW-FET nanosensor array on microneedle elements. Using this technology, ISF-borne metabolites require no extraction and are measured directly and continuously by the nanosensors. Due to their chemical sensing mechanism, the nanosensor response is only influenced by the specific metabolite of interest, and no response is observed in the presence of potential exogenous and endogenous interferents known to seriously affect the response of current electrochemical glucose detection approaches. The 2D architecture of this platform, using a single SOI substrate as a top-down multipurpose material, resulted in a standard fabricated chip with 3D functionality. After proving the ability of the system to act as a selective multimetabolites sensor, we have implemented our platform to reach our main goal for in vivo continuous glucose monitoring of healthy human subjects. Furthermore, minor adjustments to the fabrication technique allow the on-chip integration of microinjection needle elements, which can ideally be used as a drug delivery system. Preliminary experiments on a mice animal model successfully demonstrated the single-chip capability to both monitor glucose levels as well as deliver insulin. By that, we hope to provide in the future a cost-effective and reliable wearable personalized clinical tool for patients and a strong tool for research, which will be able to perform direct monitoring of clinical biomarkers in the ISF as well as synchronized transdermal drug delivery by this single-chip multifunctional platform.

Closed-loop artificial endocrine pancreas from Japan.

The development of a closed-loop artificial pancreas (AP) in the Western countries and Japan is different. In Western countries, wearable AP with a closed-loop glycemic control system has been developed as a treatment for patients with type 1 and type 2 diabetes. On the contrary, in Japan, bedside closed-loop AP explored by a Japanese company (Nikkiso, Tokyo, Japan) has developed as perioperative glycemic control device in surgical patients and acute care patients with emergency. In this article, we reviewed the scientific evidence in the past and present and future prospects of perioperative glycemic control using bedside AP with a closed-loop system in Japan. Conventional perioperative strict glycemic controls have three major problems: hyperglycemia, hypoglycemia, and variability in blood glucose concentrations. In Japan, perioperative strict glycemic control using the current bedside AP STG-55 (Nikkiso, Tokyo, Japan) has been developed since 2010. This novel glycemic control method achieved not only stable glycemic control without hyperglycemia, hypoglycemia, and less variability of blood glucose concentrations but also reduced postoperative infectious complications in patients undergoing major surgeries. Among the rapidly increasing number of surgical or emergency patients with diabetes, frailty, and sarcopenia of intrinsic glucose intolerance, more sophisticated and smaller AP available easily in operating rooms and intensive care units will be warranted to promote improved therapeutic outcomes in such critically ill patients.

Current status and issues of the artificial pancreas: abridged English translation of a special issue in Japanese.

Surgical stress induces hyperglycemia and gives rise to glucose toxicity, which causes infectious diseases, resulting in unfavorable surgical outcomes. Intensive insulin treatment can control short- and long-term complications in patients with not only diabetes mellitus, but also surgical diabetes; however, it is associated with an increased risk of hypoglycemia. The wearable artificial pancreas was originally developed to control glucose levels in patients with type 1 diabetes, progressing to a device with enhanced stability and safety for these patients. Its usability has further progressed to include patients with type 2 diabetes. The bedside artificial pancreas is the only closed-loop-type artificial pancreas which can maintain stable glycemic control in accordance with a target blood glucose range, based on the patient's actual blood glucose levels. Moreover, this stable glycemic control with a low variation in blood glucose concentration within the target range is produced without any hypoglycemia. Significant advances of this device will now occur due to the approval of treatment for perioperative glycemic control by the Japanese Health Care Insurance System in 2016. Along with an increase in the number of mainly elderly patients with low glucose tolerance, it is expected that the role of the artificial pancreas will increase in the future. Considering the current state and expense of regenerative and transplant medicine, along with donor shortages, further development of the artificial pancreas and associated glycemic control can be expected.

Individually Adaptive Artificial Pancreas in Subjects with Type 1 Diabetes: A One-Month Proof-of-Concept Trial in Free-Living Conditions

Abstract Background: To evaluate the efficacy of a run-to-run (R2R) adaptive wearable artificial pancreas (AP) after 1 month of closed-loop glucose control in subjects with type 1 diabetes (T1D) under free-living conditions. Methods: Eighteen adults, who had previously completed a 1-month closed-loop study with a non-adaptive artificial pancreas (NA-AP), volunteered for an additional 1-month extension study in which the AP was equipped with an adaptive model predictive control algorithm (R2R-AP). Continuous glucose monitoring data were analyzed on an intention-to-treat basis by comparing the last week of R2R-AP versus the last week of NA-AP. The primary endpoint was the time in target range (3.9–10 mmol/L) over 24 h. Results: Time in target with R2R-AP is higher than with the NA-AP, although the increase was not significant: mean 66.90% (standard deviation: 13.34) versus 61.82% (11.12), P = 0.10. The increase was significant during the night: 74.01% (14.61) versus 64.31% (15.71), P = 0.03, and at wake-up ...

Current topics in glycemic control by wearable artificial pancreas or bedside artificial pancreas with closed-loop system.

The incidence of diabetes is increasing at an unprecedented pace and has become a serious health concern worldwide during the last two decades. Despite this, adequate glycemic control using an artificial pancreas has not been established, although the 21st century has seen rapid developments in this area. Herein, we review current topics in glycemic control for both the wearable artificial pancreas for type 1 and type 2 diabetic patients and the bedside artificial pancreas for surgical diabetic patients. In type 1 diabetic patients, nocturnal hypoglycemia associated with insulin therapy remains a serious problem that could be addressed by the recent development of a wearable artificial pancreas. This smart phone-like device, comprising a real-time, continuous glucose monitoring system and insulin pump system, could potentially significantly reduce nocturnal hypoglycemia compared with conventional glycemic control. Of particular interest in this space are the recent inventions of a low-glucose suspend feature in the portable systems that automatically stops insulin delivery 2h following a glucose sensor value<70mg/dL and a bio-hormonal pump system consisting of insulin and glucagon pumps. Perioperative tight glycemic control using a bedside artificial pancreas with the closed-loop system has also proved safe and effective for not only avoiding hypoglycemia, but also for reducing blood glucose level variability resulting in good surgical outcomes. We hope that a more sophisticated artificial pancreas with closed-loop system will now be taken up for routine use worldwide, providing enormous relief for patients suffering from uncontrolled hyperglycemia, hypoglycemia, and/or variability in blood glucose concentrations.

Day-and-Night Closed-Loop Glucose Control in Patients With Type 1 Diabetes Under Free-Living Conditions: Results of a Single-Arm 1-Month Experience Compared With a Previously Reported Feasibility Study of Evening and Night at Home.

After testing of a wearable artificial pancreas (AP) during evening and night (E/N-AP) under free-living conditions in patients with type 1 diabetes (T1D), we investigated AP during day and night (D/N-AP) for 1 month. Twenty adult patients with T1D who completed a previous randomized crossover study comparing 2-month E/N-AP versus 2-month sensor augmented pump (SAP) volunteered for 1-month D/N-AP nonrandomized extension. AP was executed by a model predictive control algorithm run by a modified smartphone wirelessly connected to a continuous glucose monitor (CGM) and insulin pump. CGM data were analyzed by intention-to-treat with percentage time-in-target (3.9-10 mmol/L) over 24 h as the primary end point. Time-in-target (mean ± SD, %) was similar over 24 h with D/N-AP versus E/N-AP: 64.7 ± 7.6 vs. 63.6 ± 9.9 (P = 0.79), and both were higher than with SAP: 59.7 ± 9.6 (P = 0.01 and P = 0.06, respectively). Time below 3.9 mmol/L was similarly and significantly reduced by D/N-AP and E/N-AP versus SAP (both P < 0.001). SD of blood glucose concentration (mmol/L) was lower with D/N-AP versus E/N-AP during whole daytime: 3.2 ± 0.6 vs. 3.4 ± 0.7 (P = 0.003), morning: 2.7 ± 0.5 vs. 3.1 ± 0.5 (P = 0.02), and afternoon: 3.3 ± 0.6 vs. 3.5 ± 0.8 (P = 0.07), and was lower with D/N-AP versus SAP over 24 h: 3.1 ± 0.5 vs. 3.3 ± 0.6 (P = 0.049). Insulin delivery (IU) over 24 h was higher with D/N-AP and SAP than with E/N-AP: 40.6 ± 15.5 and 42.3 ± 15.5 vs. 36.6 ± 11.6 (P = 0.03 and P = 0.0004, respectively). D/N-AP and E/N-AP both achieved better glucose control than SAP under free-living conditions. Although time in the different glycemic ranges was similar between D/N-AP and E/N-AP, D/N-AP further reduces glucose variability.

Randomized Summer Camp Crossover Trial in 5- to 9-Year-Old Children: Outpatient Wearable Artificial Pancreas Is Feasible and Safe.

The Pediatric Artificial Pancreas (PedArPan) project tested a children-specific version of the modular model predictive control (MMPC) algorithm in 5- to 9-year-old children during a camp. A total of 30 children, 5- to 9-years old, with type 1 diabetes completed an outpatient, open-label, randomized, crossover trial. Three days with an artificial pancreas (AP) were compared with three days of parent-managed sensor-augmented pump (SAP). Overnight time-in-hypoglycemia was reduced with the AP versus SAP, median (25(th)-75(th) percentiles): 0.0% (0.0-2.2) vs. 2.2% (0.0-12.3) (P = 0.002), without a significant change of time-in-target, mean: 56.0% (SD 22.5) vs. 59.7% (21.2) (P = 0.430), but with increased mean glucose 173 mg/dL (36) vs. 150 mg/dL (39) (P = 0.002). Overall, the AP granted a threefold reduction of time-in-hypoglycemia (P < 0.001) at the cost of decreased time-in-target, 56.8% (13.5) vs. 63.1% (11.0) (P = 0.022) and increased mean glucose 169 mg/dL (23) vs. 147 mg/dL (23) (P < 0.001). This trial, the first outpatient single-hormone AP trial in a population of this age, shows feasibility and safety of MMPC in young children. Algorithm retuning will be performed to improve efficacy.

The artificial pancreas: a digital-age treatment for diabetes

The artificial pancreas—the commonly accepted term for closed-loop glucose control—combines a continuous glucose monitor, insulin pump, and control algorithm into a system that automates insulin delivery. In The Lancet Diabetes & Endocrinology, Hood Thabit and colleagues' 1 Thabit H Lubina-Solomon A Stadler M et al. Home use of closed-loop insulin delivery for overnight glucose control in adults with type 1 diabetes: a 4-week, multicentre, randomised crossover study. Lancet Diabetes Endocrinol. 2014; (published online June 16.)http://dx.doi.org/10.1016/S2213-8587(14)70114-7 Google Scholar multicentre, randomised crossover study assesses home-based use of overnight closed-loop insulin delivery for improvement of glucose control in 25 participants with type 1 diabetes. Extending previous work by the same group, 2 Hovorka R Allen JM Elleri D et al. Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomised crossover trial. Lancet. 2010; 375: 743-751 Summary Full Text Full Text PDF PubMed Scopus (396) Google Scholar the artificial pancreas system in the present study was automated, rather than manual, and was used by patients at home for 4 weeks. At-home use is a particularly notable aspect because in other outpatient trials the device was used in a controlled environment, 3 Kovatchev BP Renard E Cobelli C et al. Feasibility of outpatient fully integrated closed-loop control: first studies of wearable artificial pancreas. Diabetes Care. 2013; 36: 1851-1858 Crossref PubMed Scopus (153) Google Scholar , 4 Phillip M Battelino T Atlas E et al. Nocturnal glucose control with an artificial pancreas at a diabetes camp. N Engl J Med. 2013; 368: 824-833 Crossref PubMed Scopus (337) Google Scholar and only one trial 5 Nimri R Muller I Atlas E et al. Night glucose control with MD-Logic artificial pancreas in home setting: a single blind, randomized crossover trial-interim analysis. Pediatr Diabetes. 2014; 15: 91-99 Crossref PubMed Scopus (83) Google Scholar reported overnight closed-loop glucose control at home. Home use of closed-loop insulin delivery for overnight glucose control in adults with type 1 diabetes: a 4-week, multicentre, randomised crossover studyUnsupervised overnight closed-loop insulin delivery at home is feasible and could improve glucose control in adults with type 1 diabetes. Full-Text PDF Open Access

The Future of Closed Loop

The Future of Closed Loop

Feasibility of Outpatient Fully Integrated Closed-Loop Control

OBJECTIVETo evaluate the feasibility of a wearable artificial pancreas system, the Diabetes Assistant (DiAs), which uses a smart phone as a closed-loop control platform.RESEARCH DESIGN AND METHODSTwenty patients with type 1 diabetes were enrolled at the Universities of Padova, Montpellier, and Virginia and at Sansum Diabetes Research Institute. Each trial continued for 42 h. The United States studies were conducted entirely in outpatient setting (e.g., hotel or guest house); studies in Italy and France were hybrid hospital–hotel admissions. A continuous glucose monitoring/pump system (Dexcom Seven Plus/Omnipod) was placed on the subject and was connected to DiAs. The patient operated the system via the DiAs user interface in open-loop mode (first 14 h of study), switching to closed-loop for the remaining 28 h. Study personnel monitored remotely via 3G or WiFi connection to DiAs and were available on site for assistance.RESULTSThe total duration of proper system communication functioning was 807.5 h (274 h in open-loop and 533.5 h in closed-loop), which represented 97.7% of the total possible time from admission to discharge. This exceeded the predetermined primary end point of 80% system functionality.CONCLUSIONSThis study demonstrated that a contemporary smart phone is capable of running outpatient closed-loop control and introduced a prototype system (DiAs) for further investigation. Following this proof of concept, future steps should include equipping insulin pumps and sensors with wireless capabilities, as well as studies focusing on control efficacy and patient-oriented clinical outcomes.

Comparison of control algorithms for the blood glucose concentration in a virtual patient with an artificial pancreas

To obtain the most suitable control algorithm for a wearable artificial pancreas, different control algorithms were compared and tested using a Hovorka model. Model predictive control (MPC), linear and nonlinear model forms, proportional integral derivative control (PID), neural-network-based model predictive control (NN-MPC), nonlinear autoregressive moving average (NARMA-L2) and sequential quadratic programming (SQP) were evaluated using the Hovorka model. Due to the fact that modeling of biomedical processes are very complex, to present the most effective control algorithm, various control strategies were needed to application. In the control algorithms, set point tracking and disturbance rejection were performed. With respect to the rise times of the control algorithms, SQP with optimal control had the shortest time, and NARMA-L2 had the longest time. Because the control algorithm connects the glucose meter and the insulin pump in an artificial pancreas, the rise time is the most important parameter. We propose that optimal control with SQP is the most suitable control algorithm to connect the glucose meter and the insulin pump.

The next generation of artificial pancreas control algorithms.

Creating a wearable artificial pancreas (AP) by closing the loop between a glucose sensor and an insulin infusion pump has the potential to significantly impact the complications associated with and improve the quality of life of diabetic individuals. Despite recent progress on glucose sensor and insulin infusion technologies, control algorithms built on the simple glucose value efferent and insulin dose afferent model are not efficient and reliable. Based on glucose regulatory mechanisms known to date, their impairment in the diabetic state, and fundamental principles of control theory, some corrections to the present course of research are proposed to facilitate the removal of this barrier. A greater emphasis on model predictive controllers or controllers that exploit a mathematical representation, or model, of the patient's own physiology is proposed. Whole-body physiologically based pharmacokinetics-pharmacodynamics-type models hold the best odds for enabling a successful closed-loop AP. However, two major improvements to the diabetes modeling state of the art are required to make them practical for daily care: integrating hypothalamus-pituitary-adrenal axis and gastrointestinal tract submodels. Although there are simple representations of these in current existence, large concerted efforts between experimentalists and modelers will be required to enhance their accuracy. Finally, changes in hardware that complements controller performance are suggested. For instance, the development of dual control inputs of insulin and glucagon could relax tolerances on controller accuracy.

Virtual type 1 diabetic patient for feedback control systems

Research and development of an external wearable artificial pancreas, although improved by recent technology achievements, still require simulation tools like the mathematical model introduced in the present study. The aim was to realize a mathematical model of insulin and glucose metabolism in type I diabetes and to test its effectiveness for development and assessment of control algorithms. A Proportional-Derivative-2nd derivative (PDD2) control algorithm was tested on a “virtual patient” constituted by the previously developed mathematical model simulating the patient response to a standard meal (90 g of carbohydrates, then increased and decreased). PDD2 controller performances were compared with the results of standard therapy (preprandial bolus) in continuous subcutaneous insulin infusion therapy (CSII). Area under the curve of glycaemic response ( QG) and hyperglicemia duration ( Durat) were chosen as performance indexes. In response to medium-light meals PDD2 reduced 35% of Durat and 25% of QG in respect to standard therapy. The average values of model estimated parameters on a cluster of patients give a virtual patient that supports the design and testing of control algorithms, improving the expectations and reducing the risk of experimental activities. PDD2 seems a very promising control strategy that can improve post-prandial behaviour in respect to standard therapy.

Model Based Study on Monitoring Ketone Bodies to Improve Safety in Intensive Insulin Therapy

The present study explores new signals (capillary 3betahydroxybutyrate - 3betaOHB) for improving the safety of a closed loop insulin infusion system (external wearable artificial pancreas). Data collected during a clinical trial on diabetic subjects including a period of insulin deprivation were interpreted through mathematical models to simulate the effect of monitoring ketone bodies (capillary 3betaOHB, KB) compared to blood glucose in subjects on Continuous Subcutaneous Insulin Infusion (CSII) treatment. The estimation of model coefficients satisfactorily fits experimental data. The evaluation of dynamic changes of capillary 3betaOHB levels showed a more rapid response than blood glucose. The effect of the combination of monitoring of glucose and ketone bodies can consistently improve the safety and efficacy of the use of a closed loop system for glycemic control in dangerous situations like ketoacidosis. If a subcutaneous glucose-ketone bodies sensor were to become available in the near future it would be a key component of an external artificial pancreas.

Evaluation of glucose controllers in virtual environment: methodology and sample application

Adaptive systems to deliver medical treatment in humans are safety-critical systems and require particular care in both the testing and the evaluation phase, which are time-consuming, costly, and confounded by ethical issues. The objective of the present work is to develop a methodology to test glucose controllers of an artificial pancreas in a simulated (virtual) environment. A virtual environment comprising a model of the carbohydrate metabolism and models of the insulin pump and the glucose sensor is employed to simulate individual glucose excursions in subjects with type 1 diabetes. The performance of the control algorithm within the virtual environment is evaluated by considering treatment and operational scenarios. The developed methodology includes two dimensions: testing in relation to specific life style conditions, i.e. fasting, post-prandial, and life style (metabolic) disturbances; and testing in relation to various operating conditions, i.e. expected operating conditions, adverse operating conditions, and system failure. We define safety and efficacy criteria and describe the measures to be taken prior to clinical testing. The use of the methodology is exemplified by tuning and evaluating a model predictive glucose controller being developed for a wearable artificial pancreas focused on fasting conditions. Our methodology to test glucose controllers in a virtual environment is instrumental in anticipating the results of real clinical tests for different physiological conditions and for different operating conditions. The thorough testing in the virtual environment reduces costs and speeds up the development process.