Towards the Integration of an Islet-Based Biosensor in Closed-Loop Therapies for Patients With Type 1 Diabetes

Abstract

In diabetes mellitus (DM) treatment, Continuous Glucose Monitoring (CGM) linked with insulin delivery becomes the main strategy to improve therapeutic outcomes and quality of patients’ lives. However, Blood Glucose (BG) regulation with CGM is still hampered by limitations of algorithms and glucose sensors. Regarding sensor technology, current electrochemical glucose sensors do not capture the full spectrum of other physiological signals, i.e., lipids, amino acids or hormones, relaying the general body status. Regarding algorithms, variability between and within patients remains the main challenge for optimal BG regulation in closed-loop therapies. This work highlights the simulation benefits to test new sensing and control paradigms which address the previous shortcomings for Type 1 Diabetes (T1D) closed-loop therapies. The UVA/Padova T1DM Simulator is the core element here, which is a computer model of the human metabolic system based on glucose-insulin dynamics in T1D patients. That simulator is approved by the US Food and Drug Administration (FDA) as an alternative for pre-clinical testing of new devices and closed-loop algorithms. To overcome the limitation of standard glucose sensors, the concept of an islet-based biosensor, which could integrate multiple physiological signals through electrical activity measurement, is assessed here in a closed-loop insulin therapy. This investigation has been addressed by an interdisciplinary consortium, from endocrinology to biology, electrophysiology, bio-electronics and control theory. In parallel to the development of an islet-based closed-loop, it also investigates the benefits of robust control theory against the natural variability within a patient population. Using 4 meal scenarios, numerous simulation campaigns were conducted. The analysis of their results then introduces a discussion on the potential benefits of an Artificial Pancreas (AP) system associating the islet-based biosensor with robust algorithms.

A Review on artificial pancreas mathematical models

“…Experts from a variety of disciplines, including endocrinology, biology, electrophysiology, bio-electronics, and control theory, are involved in this interdisciplinary inquiry. The UVA/Padova T1DM is used by them [8].…”

“…The second article introduces a cutting-edge hybrid artificial pancreas system that successfully handles issues associated with unexpected meals thanks to customized control methods and the incorporation of an automatic Bolus Priming System. These studies show the potential to improve diabetes treatment and patient outcomes by using simulation techniques and the UVA/Padova simulator for evaluation and validation [8], [9]. The goal of type 1 diabetes research has been to create efficient insulin delivery systems that replicate endogenous insulin secretion.…”

Continuous monitoring of glucose levelsin vivowith a micro-organ based microfluidic biosensor

“…The profiles of the electrical responses can be introduced in an FDA validated human simulator, the UVA-PADOVA T1DMS, to regulate metabolism in this in-silico model. [15–16] Thus, the electrical profiling in extracorporeal islet activity, as measured here, can be transposed to regulation of glucose metabolism in humans to analyse ensuing metabolic consequences.…”

“…Within this in silico model, an islet biosensor-based artificial pancreas was as efficient as standard CGMs and even outperformed them under challenging conditions. [16]…”

Developing the UVA/Padova Type 1 Diabetes Simulator: Modeling, Validation, Refinements, and Utility

“…While it is not possible to review all uses of this simulation environment to date, we include a sample to 30 publications spanning 12 years, all of which used the UVA/Padova simulator as a central tool for their developments. 82-111 Overall, a PubMed search (Figure 5) shows that since the introduction of the Minimal Model in 1979, about 555 papers were published on the topics of closed-loop control of diabetes or AID algorithms. Two notable dates mark the beginning of these developments: The 2005 National Institutes of Health (NIH)/Juvenile Diabetes Research Foundation (JDRF)/FDA workshop “Obstacles and Opportunities on the Road to Artificial Pancreas: Closing the Loop” and the 2008 acceptance of the UVA/Padova simulator as a substitute to animal trials for the development of closed-loop algorithms.…”