Principle and performance of Concanavalin A-sugar affinity based closed-loop insulin delivery system

Abstract

A closed-loop control system that delivers insulin in response to a change of the glucose level is a highly desirable therapy for diabetes patients. An example of such a system is the Concanavalin A (Con A)-sugar affinity based chemically controlled closed-loop insulin delivery system (Con A-based system in short) that integrates a glucose sensing element and a glucose-triggered insulin release system into a single system using glucose-responsive materials. This thesis concerns this system, primarily focusing on the principle or mechanism of the Con A-based system owing to the controversy regarding the principle that the affinity of glucose with Con A is much lower than that of polysaccharides with Con A and therefore glucose cannot trigger the dissociation of Con A-polysaccharides binding in the current literature. The other focus of this thesis is on the feasibility of tailored design to individual patients.

Four specific research objectives were defined for this thesis. Objective 1: Investigate the glucose-responsive principle of Con A-sugar affinity-based hydrogel networks with the characterization methods such as isothermal titration calorimetry and attempt to resolve the aforementioned controversy. Objective 2: Examine the feasibility of modulating the insulin release behavior by varying the composition of the Con A-based system. Objective 3: Develop a methodology for design of the Con A-based system to tailor to individual patients in order to prolong the insulin supply period. Objective 4: Develop a mathematical model for improving the design in Objective 3.

The study involves both experiments and mathematical modeling, including analysis with the isothermal titration calorimetry method, and use of the ligand binding equilibrium theory. As well, the study attempts to develop a robotic system perspective to the insulin delivery system. The following conclusions can be drawn from the study: (1) the robotic system perspective to drug delivery systems can provide a general framework for systematic study of drug delivery systems; (2) the principle of glucose triggering the dissociation of Con A-sugar networks is valid because (a) the glucose molecules and the terminal groups (on DexG) have a similar binding affinity with Con A sites and (b) the glucose can bind with the remaining Con A sites based on the ligand binding equilibrium theory; (3) the amount of remaining Con A sites and DexG molecules after the formation of the Con A-DexG network can be determined, so a modulated insulin release is possible; (4) an integrated design of chemically controlled closed-loop insulin delivery system, specifically by integration of Con A-based glucose-responsive microspheres into a biodegradable chitosan scaffold, can prolong the insulin supply period; (5) a mathematical model for the Con A-based system controlled by swelling and variable diffusion theory has been established and validated, so the glucose-responsive behavior of Con A-DexG hydrogel can be predicted with the model.

There are a couple of contributions with this thesis. First, a systems perspective to drug delivery is available, which can help to design a hybrid (chemical, mechanical) intelligent drug delivery system. Second, the principle of Con A-sugar affinity-based hydrogel networks has been confirmed along with the resolution of the existing controversy on how and why the Con A-based system works. Third, a modulated insulin release with a prolonged supply duration is demonstrated, which opens room for personalized insulin delivery. Finally, a mathematical model with two variables (swelling ratio and diffusion coefficient) is available in the field of insulin delivery, which is an indispensable tool for the design of individualized delivery systems.

In further studies, several aspects may be considered as follows: (1) improvement of the mathematical model for the Con A-based system; (2) combination of glucose level and the characteristics of patients that are responsible for individual requirements for personalized design; (3) optimization of the design to improve the stability, reliability, robustness and/or resilience of the system; (4) incorporation of different insulin sources in the chemically controlled closed-loop system to improve the sustainability of insulin delivery.