Automated insulin delivery systems

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Automated insulin delivery systems are automated (or semi-automated) systems designed to assist people with diabetes, primarily type 1, by automatically adjusting insulin delivery to help them control their blood glucose levels. Currently available systems (as of October, 2020) can only deliver (and regulate delivery of) a single hormone- insulin. Other systems currently in development aim to improve on current systems by adding one or more additional hormones that can be delivered as needed, providing something closer to the endocrine functionality of a healthy pancreas.

Contents

The endocrine functionality of the pancreas is provided by islet cells which produce the hormones insulin and glucagon. Artificial pancreatic technology mimics the secretion of these hormones into the bloodstream in response to the body's changing blood glucose levels. Maintaining balanced blood sugar levels is crucial to the function of the brain, liver, and kidneys. [1] Therefore, for type 1 patients, it is necessary that the levels be kept balanced when the body cannot produce insulin itself. [1]

Automated insulin delivery systems are often referred to using the term artificial pancreas, but the term has no precise, universally accepted definition. For uses other than automated insulin delivery, see Artificial pancreas (disambiguation).

General Overview

History

The first automated insulin delivery system was known as the Biostator.

Classes of AID systems

Currently available AID systems fall into four broad classes based on their capabilities. The first systems released- suspend systems- can only halt insulin delivery. Loop systems can modulate delivery both up and down.

Threshold suspend

Threshold suspend systems are the simplest form of insulin delivery automation. They halt the constant flow of insulin from a pump (known as basal insulin) when a connected CGM reports a glucose level below a pre-set threshold. Halting basal delivery stops the normal preprogrammed rate of delivery, but it cannot remove insulin that has already been infused, so the overall efficacy of threshold suspend systems is limited due to the relatively slow pharmacokinetics of insulin delivered subcutaneously.

Predictive Low Glucose Suspend

A step forward from threshold suspend systems, Predictive Low Glucose Suspend (PLGS) systems use a mathematical model to extrapolate predicted future blood sugar levels based on recent past readings from a CGM. This allows the system to halt insulin delivery as much as 30 minutes prior to a predicted hypoglycemic event, allowing addition time for the slow pharmacokinetics of insulin to reflect that delivery has been halted.

Hybrid Closed Loop

Hybrid Closed Loop (HCL) systems further expand on the capabilities of PGLS systems by adjusting basal insulin delivery rates both up and down in response to values from a continuous glucose monitor. Through this modulation of basal insulin, the system is able to reduce the magnitude and duration both hyperglycemic and hypoglycemic events.

Advanced Hybrid Closed Loop

In addition to modulating basal insulin, Advanced Hybrid Closed Loop systems have the ability to deliver boluses of insulin to correct for elevated blood sugar.

Required Components

An automated insulin delivery system consists of three distinct components: a continuous glucose monitor to determine blood sugar levels, a pump to deliver insulin, and an algorithm that uses the data from the CGM to send commands to the pump. In the United States, the Food and Drug Administration (FDA) allows each component to be approved independently, allowing for more rapid approvals and incremental innovation. Each component is discussed in greater detail below.

Continuous Glucose Monitor (CGM)

Artificial pancreas feedback system Artificial Pancreas.jpg
Artificial pancreas feedback system

Continuous glucose monitors (CGMs) are medical devices which extrapolate an estimate of the glucose concentration in a patient's blood based on the level of glucose present in the subcutaneous interstitial fluid. A thin, biocompatible sensor wire coated with a glucose-reactive enzyme is inserted into the skin, allowing the system to read the voltage generated, and based on it, estimate blood glucose. The biggest advantage of a CGM over a traditional fingerstick blood glucose meter is that the CGM can take a new reading as often as every 60 seconds (although most only take a reading every 5 minutes), allowing for a sampling frequency that is able to provide not just a current blood sugar level, but a record of past measurements; allowing computer systems to project past short-term trends into the future, showing patients where their blood sugar levels are likely headed.

Early CGMs were not particularly accurate, but were still useful for observing and recording overall trends and provide warnings in the event of rapid changes in blood glucose readings.

Continuous blood glucose monitors are one of the set of devices that make up an artificial pancreas device system, the other being an insulin pump, and a glucose meter to calibrate the device. [2] Continuous glucose monitors are a more recent breakthrough and have begun to hit the markets for patient use after approval from the FDA. Both the traditional and the continuous monitor require manual insulin delivery or carbohydrate intake depending on the readings from the devices. While the traditional blood glucose meters require the user to prick their finger every few hours to obtain data, continuous monitors use sensors placed just under the skin on the arm or abdomen to deliver blood sugar level data to receivers or smartphone apps as often as every few minutes. [3] The sensors can be used for up to fourteen days. A number of different continuous monitors are currently approved by the FDA. [4]

The first continuous glucose monitor (CGM) was approved in December 2016. Developed by Dexcom, the G5 Mobile Continuous Monitoring System requires users to prick their fingers twice a day (as opposed to the typical average 8 times daily with the traditional meters) in order to calibrate the sensors. The sensors last up to seven days. The device uses Bluetooth technology to warn the user either through a handheld receiver or app on a smartphone if blood glucose levels reach below a certain point. The cost for this device excluding any co-insurance is an estimated $4,800 a year. [4]

Blood glucose meter FreeStyle Libre from Abbott. BGM twopart.JPG
Blood glucose meter FreeStyle Libre from Abbott.

Abbott Laboratories' FreeStyle Libre CGM was approved in September 2017. Recently, the technology was modified to support smartphone use through the LibreLink app. This device does not require finger pricks at all and the sensor, placed on the upper arm, lasts 14 days. The estimated cost for this monitor is $1,300 a year. [4]

Dexcom's next G6 model CGM was approved in March 2018, which can last up to ten days and does not need finger prick calibration. Like Medtronic's monitor, it can predict glucose level trends. It is compatible for integration into insulin pumps. [4]

Control Algorithm

Insulin Pump

Currently Available Systems

Do-It-Yourself

Commercial

MiniMed 670G

In September 2016, the FDA approved the Medtronic MiniMed 670G, which was the first approved hybrid closed loop system. The device senses a diabetic person's basal insulin requirement and automatically adjusts its delivery to the body. [5] It is made up of a continuous glucose monitor, an insulin pump, and a glucose meter for calibration. It automatically functions to modify the level of insulin delivery based on the detection of blood glucose levels by continuous monitor. It does this by sending the blood glucose data through an algorithm that analyzes and makes the subsequent adjustments. [5] The system has two modes. Manual mode lets the user choose the rate at which basal insulin is delivered. Auto mode regulates basal insulin levels from the continuous monitor's readings every five minutes. [6]

The device was originally available only to those aged 14 or older, and in June 2018 was approved by the FDA for use in children aged 7–14. Families have reported better sleep quality from use of the new system, as they do not have to worry about manually checking blood glucose levels during the night. [7] The full cost of the system is $3700, but patients have the opportunity to get it for less. [8]

Systems in Development

Ilet Bionic Pancreas

A team at Boston University working in collaboration with Massachusetts General Hospital on a dual hormone artificial pancreas system [9] began clinical trials on their device called the Bionic Pancreas in 2008. [10] In 2016, the Public Benefit Corporation Beta Bionics was formed. In conjunction with the formation of the company, Beta Bionics changed the preliminary name for their device from the Bionic Pancreas to the iLet. [10] The device uses a closed-loop system to deliver both insulin and glucagon in response to sensed blood glucose levels. While not yet approved for public use, the 4th generation iLet prototype, presented in 2017, is around the size of an iPhone, with a touchscreen interface. It contains two chambers for both insulin and glucagon, and the device is configurable for use with only one hormone, or both. [11] While trials continue to be run, the iLet has a projected final approval for the insulin-only system in 2020. [10]

Inreda AP

In collaboration with the Academic Medical Center in Amsterdam, Inreda Diabetic B.V. has developed a closed loop system with insulin and glucagon. The initiator, Robin Koops, started to develop the device in 2004 and ran the first tests on himself. In October 2016 Inreda Diabetic B.V. got the ISO 13485 license, a first requirement to produce its artificial pancreas. [12] The product itself is called Inreda AP, and soon made some highly successful trials. After clinical trials, it received the CE marking, noting that it complies with European regulation, in February 2020. [13]

In October 2020 the health insurance company Menzis and Inreda Diabetic then started a pilot with 100 patients insured by Menzis. These are all patients that face very serious trouble in regulating their blood glucose levels. They now use the Inreda AP instead of the traditional treatment. [14] Another large scale trial with the Inreda AP was set up in July 2021, and should determine whether Dutch health insurance should cover the device for all their insured. [15] A smaller improved version of the Inreda AP is scheduled for release in 2023.

Approaches

Medical equipment

The medical equipment approach involves combining a continuous glucose monitor and an implanted insulin pump that can function together with a computer-controlled algorithm to replace the normal function of the pancreas. [16] [17] [18] The development of continuous glucose monitors has led to the progress in artificial pancreas technology using this integrated system. [19]

Closed-loop systems

Unlike the continuous sensor alone, the closed-loop system requires no user input in response to reading from the monitor; the monitor and insulin pump system automatically delivers the correct amount of hormone calculated from the readings transmitted. The system is what makes up the artificial pancreas device. [2] [3]

Current studies

Four studies on different artificial pancreas systems are being conducted starting in 2017 and going into the near future. The projects are funded by the National Institute of Diabetes and Digestive and Kidney Diseases, and are the final part of testing the devices before applying for approval for use. Participants in the studies are able to live their lives at home while using the devices and being monitored remotely for safety, efficacy, and a number of other factors. [20]

The International Diabetes Closed-Loop trial, [21] led by researchers from the University of Virginia, is testing a closed-loop system called inControl, which has a smartphone user interface. 240 people of ages 14 and up are participating for 6 months. [20]

A full-year trial led by researchers from the University of Cambridge started in May 2017 and has enrolled an estimated 150 participants of ages 6 to 18 years. [20] The artificial pancreas system being studied uses a smartphone and has a low glucose feature to improve glucose level control. [22]

The International Diabetes Center in Minneapolis, Minnesota, in collaboration with Schneider Children's Medical Center of Israel, are planning a 6-month study that will begin in early 2019 and will involve 112 adolescents and young adults, ages 14 to 30. [20] [23] The main object of the study is to compare the current Medtronic 670G system to a new Medtronic-developed system. The new system has programming that aims to improve glucose control around mealtime, which is still a big challenge in the field. [23]

The current 6-month study lead by the Bionic Pancreas team started in mid-2018 and enrolled 312 participants of ages 18 and above. [20]

Physiological

The Bio-artificial pancreas: this diagram shows a cross section of bio-engineered tissue with encapsulated islet cells which deliver endocrine hormones in response to glucose. Bio-artificial pancreas with Islet Sheet technology.JPG
The Bio-artificial pancreas: this diagram shows a cross section of bio-engineered tissue with encapsulated islet cells which deliver endocrine hormones in response to glucose.

The biotechnical company Defymed, based in France, is developing an implantable bio-artificial device called MailPan which features a bio-compatible membrane with selective permeability to encapsulate different cell types, including pancreatic beta cells. [24] The implantation of the device does not require conjunctive immuno-suppressive therapy because the membrane prevents antibodies of the patient from entering the device and damaging the encapsulated cells. After being surgically implanted, the membrane sheet will be viable for years. The cells that the device holds can be produced from stem cells rather than human donors, and may also be replaced over time using input and output connections without surgery. [24] [25] Defymed is partially funded by JDRF, formerly known as the Juvenile Diabetes Research Foundation, but is now defined as an organization for all ages and all stages of type 1 diabetes. [26] [27]

In November 2018, it was announced that Defymed would partner with the Israel-based Kadimastem, a bio-pharmaceutical company developing stem-cell based regenerative therapies, to receive a two-year grant worth approximately $1.47 million for the development of a bio-artificial pancreas that would treat type 1 diabetes. [24] [28] Kadimastem's stem cell technology uses differentiation of human embryonic stem cells to obtain pancreatic endocrine cells. These include insulin-producing beta cells, as well as alpha cells, which produce glucagon. Both cells arrange in islet-like clusters, mimicking the structure of the pancreas. [29] The aim of the partnership is to combine both technologies in a bio-artificial pancreas device, which releases insulin in response to blood glucose levels, to bring to clinical trial stages. [24]

The San Diego, California based biotech company ViaCyte has also developed a product aiming to provide a solution for type 1 diabetes which uses an encapsulation device made of a semi-permeable immune reaction-protective membrane. The device contains pancreatic progenitor cells that have been differentiated from embryonic stem cells. [30] [31] After surgical implantation in an outpatient procedure, the cells mature into endocrine cells which arrange in islet-like clusters and mimic the function of the pancreas, producing insulin and glucagon. [32] [33] The technology advanced from pre-clinical studies to FDA approval for phase 1 clinical trials in 2014, and presented two-year data from the trial in June 2018. [30] [31] They reported that their product, called PEC-Encap, has so far been safe and well tolerated in patients at a dose below therapeutic levels. The encapsulated cells were able to survive and mature after implantation, and immune system rejection was decreased due to the protective membrane. The second phase of the trial will evaluate the efficacy of the product. [30] ViaCyte has also been receiving financial support from JDRF on this project. [33]

Initiatives around the globe

In the United States in 2006, JDRF (formerly the Juvenile Diabetes Research Foundation) launched a multi-year initiative to help accelerate the development, regulatory approval, and acceptance of continuous glucose monitoring and artificial pancreas technology. [34] [35]

Grassroots efforts to create and commercialize a fully automated artificial pancreas system have also arisen directly from patient advocates and the diabetes community. [36] Bigfoot Biomedical, a company founded by parents of children with T1D have created algorithms and are developing a closed loop device that monitor blood sugar and appropriately provide insulin. [37]

Related Research Articles

Insulin pump

An insulin pump is a medical device used for the administration of insulin in the treatment of diabetes mellitus, also known as continuous subcutaneous insulin therapy. The device configuration may vary depending on design. A traditional pump includes:

Intensive insulin therapy or flexible insulin therapy is a therapeutic regimen for diabetes mellitus treatment. This newer approach contrasts with conventional insulin therapy. Rather than minimize the number of insulin injections per day, the intensive approach favors flexible meal times with variable carbohydrate as well as flexible physical activities. The trade-off is the increase from 2 or 3 injections per day to 4 or more injections per day, which was considered "intensive" relative to the older approach. In North America in 2004, many endocrinologists prefer the term "flexible insulin therapy" (FIT) to "intensive therapy" and use it to refer to any method of replacing insulin that attempts to mimic the pattern of small continuous basal insulin secretion of a working pancreas combined with larger insulin secretions at mealtimes. The semantic distinction reflects changing treatment.

Blood glucose monitoring use of a glucose monitor for testing the concentration of glucose in the blood

Blood glucose monitoring is the use of a glucose meter for testing the concentration of glucose in the blood (glycemia). Particularly important in diabetes management, a blood glucose test is typically performed by piercing the skin to draw blood, then applying the blood to a chemically active disposable 'test-strip'. Different manufacturers use different technology, but most systems measure an electrical characteristic, and use this to determine the glucose level in the blood. The test is usually referred to as capillary blood glucose.

JDRF is a nonprofit 501(c)(3) organization that funds type 1 diabetes (T1D) research, provides a broad array of community and activist services to the T1D population and actively advocates for regulation favorable to medical research and approval of new and improved treatment modalities. It was initially founded as the JDF, the Juvenile Diabetes Foundation. It later changed its name to the Juvenile Diabetes Research Foundation and is now known as JDRF.

Pramlintide

Pramlintide is an injectable amylin analogue drug for diabetes, developed by Amylin Pharmaceuticals. Pramlintide is sold as an acetate salt.

The term diabetes includes several different metabolic disorders that all, if left untreated, result in abnormally high concentration of a sugar called glucose in the blood. Diabetes mellitus type 1 results when the pancreas no longer produces significant amounts of the hormone insulin, usually owing to the autoimmune destruction of the insulin-producing beta cells of the pancreas. Diabetes mellitus type 2, in contrast, is now thought to result from autoimmune attacks on the pancreas and/or insulin resistance. The pancreas of a person with type 2 diabetes may be producing normal or even abnormally large amounts of insulin. Other forms of diabetes mellitus, such as the various forms of maturity onset diabetes of the young, may represent some combination of insufficient insulin production and insulin resistance. Some degree of insulin resistance may also be present in a person with type 1 diabetes.

Pulsatile intravenous insulin therapy, sometimes called metabolic activation therapy, or cellular activation therapy describes in a literal sense the intravenous injection of insulin in pulses versus continuous infusions. Injection of insulin in pulses mimics the physiological secretions of insulin by the pancreas into the portal vein which then drains into the liver. In healthy, non-diabetic individuals, pancreatic secretions of insulin correspond to the intake of food. The pancreas will secrete variable amounts of insulin based upon the amount of food consumed among other factors. Continuous exposure to insulin and glucagon is known to decrease the hormones’ metabolic effectiveness on glucose production in humans due to the body developing an increased tolerance to the hormones. Down-regulation at the cellular level may partially explain the decreased action of steady-state levels of insulin, while pulsatile hormone secretion may allow recovery of receptor affinity and numbers for insulin. Intermittent intravenous insulin administration with peaks of insulin concentrations may enhance suppression of gluconeogenesis and reduce hepatic glucose production.

Animas Corporation is an American company that specializes in making insulin pumps, used by people with diabetes. The company was founded by Dr. Katherine Crothall in 1996, had its initial public offering in May 2004 under the ticker symbol 'PUMP', and was ultimately acquired by Johnson & Johnson on February 18, 2006. The business is headquartered in West Chester, Pennsylvania and forms part of the Johnson & Johnson Diabetes franchise along with Lifescan and several other companies producing medical products for the treatment and management of diabetes.

Minimed Paradigm Insulin pumps

MiniMed Paradigm is a series of insulin pumps manufactured by Medtronic for patients with diabetes mellitus. The pump operates with a single AAA battery and uses a piston-plunger pump to infuse a programmed amount of insulin into the patient through a length of tubing. The Paradigm uses a one-way wireless radio frequency link to receive blood sugar measurements from select glucose meters. The Paradigm RT series adds the ability to receive data from a mated continuous blood-glucose monitor. Although the pump can use these measurements to assist in calculating a dose of insulin, no actual change in insulin delivery occurs without manual user-intervention.

DexCom, Inc. is a company that develops, manufactures, and distributes continuous glucose monitoring (CGM) systems for diabetes management. It operates internationally with headquarters in San Diego, California, and has a manufacturing facility in Mesa, Arizona.

Bruce Bode, MD, FACE is a diabetes specialist with the Atlanta Diabetes Associates in Atlanta, GA and is a clinical associate professor at Emory University in the Department of Medicine. He has served on the board of directors of the Atlanta chapters of the Juvenile Diabetes Research Foundation (JDRF), the American Diabetes Association (ADA), and various Georgia-based diabetes camps. Bode is a member of the board of directors of Glytec and an active member of the JDRF research team validating the efficacy and safety of real-time continuous glucose monitoring (CGMS), and is a former president of the ADA Georgia Affiliate and editor of the ADA's 2004 edition of Medical Management of Type 1 Diabetes.

International Diabetes Center at Park Nicollet (IDC) is a center for diabetes care, research and education located in Minneapolis, Minnesota, United States. The center provides clinical, motivational and educational services for people with diabetes. It is part of HealthPartners Institute.

Tandem Diabetes Care is an American medical device manufacturer based in San Diego, California. The company develops medical technologies for the treatment of diabetes and specifically insulin infusion therapy.

Ambulatory Glucose Profile (AGP) is a single page, standardized report for interpreting a patient's daily glucose and insulin patterns. AGP provides both graphic and quantitative characterizations of daily glucose patterns. First developed by Drs. Roger Mazze and David Rodbard, with colleagues at the Albert Einstein College of Medicine in 1987, AGP was initially used for representation of episodic self-monitored blood glucose (SMBG). The first version included a glucose median and inter-quartile ranges graphed as a 24-hour day. Dr. Mazze brought the original AGP to the International Diabetes Center (IDC) in the late 1980s and since that time, IDC has built the AGP into the internationally recognized standard for glucose pattern reporting.

Bigfoot Biomedical Inc. is a medical technology startup headquartered in Milpitas, California, founded by a team of people with personal connections to type 1 and type 2 diabetes.

Boris P. Kovatchev is a scientist at the University of Virginia, director of the UVA Center for Diabetes Technology, and a principal investigator of the JDRF Artificial Pancreas Project.

Nightscout is a free and open-source project, and associated social movement, that enables accessing and working with continuous glucose monitor (CGM) data. Nightscout software aims to give users access to their real time blood sugar data by putting this data in the cloud. In addition to browser-based data visualization, Nightscout can also be used to review data from a phone or smartwatch, or to remotely monitor CGM data for individuals with type 1 diabetes. Associated with Nightscout software is a broader "CGM in the Cloud" social movement, supporting individuals seeking to access and use realtime CGM data through commercial and DIY approaches.

The Open Artificial Pancreas System (OpenAPS) project is a free and open-source project that aims to make basic artificial pancreas system (APS) technology available to everyone. The OpenAPS project was designed with the idea of quickly getting the APS technology to more people using a direct approach, rather than waiting for clinical trials to be completed and FDA approval to be granted as is traditional.

Continuous glucose monitor

A continuous glucose monitor (CGM) is a device used for monitoring blood glucose on a continual basis by insulin-requiring people with diabetes, e.g. people with type I, type II diabetes or other types of diabetes. A continuous glucose monitor consists of three parts: a small electrode placed under the skin, a transmitter sending readings at regular intervals, and a separate receiver. Currently approved CGMs use an enzymatic technology which reacts with glucose molecules in the interstitial fluid generating an electric current. This electric current is then relayed from a transmitter attached to the sensor out to a reader which displays the data to the patient.

Robin Koops is a Dutch mechanical engineer, designer and inventor. He is known for developing an artificial pancreas.

References

Notes

  1. 1 2 "The Pancreas and Its Functions | Columbia University Department of Surgery". columbiasurgery.org. Retrieved 2018-11-07.
  2. 1 2 Health, Center for Devices and Radiological. "Artificial Pancreas Device System - What is the pancreas? What is an artificial pancreas device system?". www.fda.gov. Retrieved 2018-11-27.
  3. 1 2 Elleri D, Dunger DB, Hovorka R (November 2011). "Closed-loop insulin delivery for treatment of type 1 diabetes". BMC Medicine. 9 (1): 120. doi:10.1186/1741-7015-9-120. PMC   3229449 . PMID   22071283.
  4. 1 2 3 4 "The First Four Continuous Glucose Monitors". Managed Care magazine. 2018-07-04. Retrieved 2018-11-07.
  5. 1 2 Health, Center for Devices and Radiological. "Recently-Approved Devices - The 670G System - P160017". wayback.archive-it.org. Archived from the original on 2017-01-11. Retrieved 2018-11-07.
  6. ↑ "MiniMed 670G Insulin Pump System | World's First Hybrid Closed Loop System". www.medtronicdiabetes.com. Retrieved 2018-11-07.
  7. ↑ "FDA Approves the MiniMed 670G System for Children 7-13 - The LOOP Blog". www.medtronicdiabetes.com. 2018-06-22. Retrieved 2018-11-07.
  8. ↑ "Update on MiniMed 670G Availability". www.medtronicdiabetes.com. Retrieved 2018-11-07.
  9. ↑ "bionicpancreas.org". www.bionicpancreas.org. Retrieved 2018-11-07.
  10. 1 2 3 "Update on the iLet Bionic Pancreas Closed Loop System". Healthline. Retrieved 2018-11-07.
  11. ↑ "Bionic Pancreas Passes Critical Science Hurdle | BU Today | Boston University". BU Today. Retrieved 2018-11-07.
  12. ↑ "CE certification is halfway!". inreda diabetic. Retrieved 2021-09-26.
  13. ↑ Blauw 2020.
  14. ↑ "Kunstmatige alvleesklier: meer vrijheid voor mensen met diabetes type 1". Menzis. 6 October 2020. Retrieved 25 September 2021.
  15. ↑ diabetestype1 (13 July 2021). "Nieuw onderzoek naar de kunstalvleesklier mogelijk dankzij grote subsidie". diabetestype1. Retrieved 25 September 2021.
  16. ↑ Gingras V, Taleb N, Roy-Fleming A, Legault L, Rabasa-Lhoret R (February 2018). "The challenges of achieving postprandial glucose control using closed-loop systems in patients with type 1 diabetes". Diabetes, Obesity & Metabolism. 20 (2): 245–256. doi:10.1111/dom.13052. PMC   5810921 . PMID   28675686.
  17. ↑ Uduku C, Oliver N (October 2017). "Pharmacological aspects of closed loop insulin delivery for type 1 diabetes". Current Opinion in Pharmacology. 36: 29–33. doi:10.1016/j.coph.2017.07.006. hdl: 10044/1/60321 . PMID   28802779.
  18. ↑ Graf A, McAuley SA, Sims C, Ulloa J, Jenkins AJ, Voskanyan G, O'Neal DN (March 2017). "Moving Toward a Unified Platform for Insulin Delivery and Sensing of Inputs Relevant to an Artificial Pancreas". Journal of Diabetes Science and Technology. 11 (2): 308–314. doi:10.1177/1932296816682762. PMC   5478040 . PMID   28264192.
  19. ↑ Apablaza P, Soto N, Codner E (May 2017). "[From insulin pump and continuous glucose monitoring to the artificial pancreas]". Revista Médica de Chile . 145 (5): 630–640. doi: 10.4067/S0034-98872017000500011 . PMID   28898340.
  20. 1 2 3 4 5 "The Miracle of an Artificial Pancreas" . Retrieved 2018-11-28.
  21. ↑ Clinical trial number NCT02844517 for "International Diabetes Closed Loop (iDCL) Trial: Research Site Training Protocol" at ClinicalTrials.gov
  22. ↑ Clinical trial number NCT02925299 for "Day and Night Closed-loop in Young People With Type 1 Diabetes" at ClinicalTrials.gov
  23. 1 2 Clinical trial number NCT03040414 for "Fuzzy Logic Automated Insulin Regulation" at ClinicalTrials.gov
  24. 1 2 3 4 "Israeli and French Biotech Companies Partner to Fight Diabetes With Bio-Artificial Pancreas". CTECH - www.calcalistech.com. 2018-11-12. Retrieved 2018-11-28.
  25. ↑ "MailPan ® BioArtificial Pancreas | Defymed, advanced therapies inspired for you". Defymed (in French). Retrieved 2018-11-28.
  26. ↑ "Innovative Medical Devices for the Treatment of Diabetes, Defymed Strengthens Its Position as a Worldwide Leader" . Retrieved 2018-11-28.
  27. ↑ Canada, JDRF. "What Does JDRF Stand For?". JDRF Canada. Retrieved 2018-11-28.
  28. ↑ "Kadimastem - Stem Cell to Cure Diseases". www.kadimastem.com. Retrieved 2018-11-28.
  29. ↑ "Diabetes - Kadimastem". www.kadimastem.com. Retrieved 2018-11-28.
  30. 1 2 3 Inc., ViaCyte. "Two-year Data from ViaCyte's STEP ONE Clinical Trial Presented at ADA 2018". www.prnewswire.com. Retrieved 2018-11-29.
  31. 1 2 "PEC‐Encap™ (VC-01™)". Viacyte, Inc. Retrieved 2018-11-29.
  32. ↑ "Home". Viacyte, Inc. Retrieved 2018-11-29.
  33. 1 2 Schulz TC (August 2015). "Concise Review: Manufacturing of Pancreatic Endoderm Cells for Clinical Trials in Type 1 Diabetes". Stem Cells Translational Medicine. 4 (8): 927–31. doi:10.5966/sctm.2015-0058. PMC   4511151 . PMID   26062982.
  34. ↑ Artificial Pancreas Project : JDRF
  35. ↑ KMorandi says (2017-08-10). "Insurers can profit while improving the lives of people with type 1 diabetes". STAT. Retrieved 2017-08-10.
  36. ↑ Hurley, Dan (24 December 2014) WIRED Magazine, Diabetes Patients Are Hacking Their Way Toward a Bionic Pancreas
  37. ↑ Knutson, Ryan (8 June 2015) The Wall Street Journal, Computer Experts Deliver Insulin to Diabetic Kids
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