M. Joan Taylor

In vivo study of a polymeric glucose-sensitive insulin delivery system using a rat model†

This study assesses the feasibility of an intraperitoneal (IP) implantable closed-loop insulin delivery device in rats, that delivers insulin via a glucose-sensitive material such that blood glucose (BG) levels are adjusted automatically to within normal tolerances. A gateway layer of this gel governs the output of insulin from an insulin reservoir device for IP implant. The performance of the system was compared over time in diabetic rats with a control system using oral glucose challenges and daily assessments of BG and body weight. The automated response of the active system was quantified using IP multiple dose injection (MDI) results in the same rat model. Successful control was found for the device containing active gel when assessed daily and when challenged with large glucose doses. This was not found when comparing an inactive gel analog as a control. The regimen was quantified by comparison with the informative MDI study. The device was well tolerated and might operate to further advantage when vascular omentum grows into the perforated front of the device. The successful device must have been outputting approximately 0.5 U/kg/h basal with 2 U/kg boosts in order to match the demand of the challenges. However, the device eventually exhausts and a refill mechanism needs to be devised in future models.

Closed-loop delivery of insulin.

The importance of exactly matching blood glucose levels in patients with diabetes mellitus with the dose and timing of insulin cannot be overemphasized. This is true for both type 1 and type 2 diabetes. The prevention of the serious consequences of diabetes should be a therapeutic goal because of the personal and national economic costs of treating the disease and its sequelae. Avoidance of sequelae cannot be achieved without so-called intensive treatment of the disease; however, this is a difficult and sometimes hazardous process. An automated and ’safe’ method of achieving intensive treatment (closed-loop insulin delivery) has been an important focus of research for many years since it was realized that the simple replacement of insulin saved the lives of patients with diabetes, but did not guarantee good health.Following the general successes of organ transplant, the obvious line of enquiry in the last three decades was to replace the pancreas with donor tissue; however, even when superseded by the simpler process of islet transplant, the benefits of this have not been widespread. This is because of the shortcomings and incompatibilities of immunosuppression with the functioning of the graft, among other problems. The two types of rejection that may occur in the presence of the autoimmune type of diabetes further endanger graft function; however, recently there have been advances that have partially solved this problem. Nevertheless, the lifetime risks of immunosuppression and the shortage of donor material still make transplant less attractive than first thought.Consequently, other approaches to closed-loop insulin delivery have been important. These include implantable pumps coupled with sensors and a range of devices incorporating glucose-sensitive materials that could be engineered into delivery systems to work by closed loop. Each of these has relative advantages and drawbacks, but some have the capacity to reach the market for clinical use. Of these, the MiniMed pump would appear to be in the lead, and is at present undergoing clinical trials that have given promising results but that have not yet entirely solved the closed-loop problem. Other designs may yet become important contenders in this interesting contest.

Diabetes Mellitus and Closed-Loop Insulin Delivery

Diabetes mellitus is presently one of the major health problems of the European and North American continents affecting at least 6% of the population. Of these, about 10% suffer from type 1, insulin-dependent disease. Diabetes, whether insulindependent or not, is a leading cause of death in developed countries (Cotran et al., 1994; McGee et al., 1992). In 1985 the World Health Organization (WHO, 1985) expert committee on diabetes defined this disease as a state of chronic hyperglycaemia, that is to say, the state of having an excessive concentration of glucose in the blood. The causes of hyperglycaemia are insulin deficiency or ineffectiveness, which leads to defective carbohydrate utilization and resultant aberrations in lipid and protein metabolism. The clinical manifestations of a patient presenting with this disease are thirst, hunger, fatigue and glucose in the urine. Depending on the stage and type, this may progress to stupor, coma and death. The symptoms may be less evident in type 2 patients in whom the secondary complications of diabetes may give rise to the presenting symptoms. The incidence of diabetes is rising sharply worldwide (Amos et al., 1997) but this is a disease that has affected man for millennia, the symptoms being described in the Ebers Papyrus of Egypt which date back to 1550 B.C. In about 200 AD., Aretaeus of Cappadocia named the disease diabetes, the Greek word meaning to flow through a siphon (Pickup and Williams, 1997). Aretaeus described diabetes as leading to a ’moist and cold wasting of the flesh and limbs into urine’. He described the disease as chronic in character, and slowly engendered, though the patient ’does not survive long when it is completely established, for the marasmus produced is rapid and death speedy’. In the 6th century, Hindu physicians recognized that the urine from the

UV Cross-Linked Dextran Methacrylate-Concanavalin A Methacrylamide Gel Materials for Self-Regulated Insulin Delivery

In this study, the successful acrylic derivatization of dextran and concanavalin A (con A) to form dextran methacrylate and con A methacrylamide is shown. These derivatized acrylic monomers are then photopolymerized in the presence of a water soluble photoinitiator Irgacure® under various conditions to form covalently bonded glucose-responsive gel materials, which undergo a transformation to sol in the presence of free glucose. Rheological data have revealed that as the degree of substitution for dextran methacrylate is increased, a more elastic material is produced due to the increased covalent linkages. Some of these gel systems show negligible component loss in in vitro diffusion experiments used to simulate the behavior of the cross-linked gel, as would be used in a self-regulated insulin delivery device.

Long-Term Stability of Glucose Responsive Dextran Methacrylate-Concanavalin A Methacrylamide Gels as Part of an Implantable Artificial Pancreas

A closed loop implantable insulin delivery device that delivers insulin to the peritoneum in an automated fashion linked to changing glucose levels has been developed and previously tested in diabetic rats and pigs. The device delivers insulin via a glucose-sensitive gel that comprises of photopolymerized acrylic derivatives of dextran and concanavalin A and acts as both a sensor and controller of the amount of insulin released. In this work the long-term stability of these acrylic polymerized gels and also dextran and concanavalin A mixtures has been shown at 20°C and 37°C by rheological characterization when stored with and without 0.1% w/w glucose. Acrylic gels were found to have a stable complex viscosity for over 730 days at these temperatures indicating that over time they do not undergo degradation. Mixtures and polymerized gels were also dialyzed in the presence of chymotrypsin, which is present in the peritoneum (device implant site) to assess gel integrity across a range of pore size dialysis membranes. Polymerized acrylic gels contained in dialysis membranes of 50 kDa were found to be resistant to degradation over a long time (>500 days). These results show that these gels would be ideal candidates as part of an implantable insulin delivery device. GRAPHICAL ABSTRACT

Glucose-sensitive gel rheology of dextran-concanavalin A mixtures suitable for self-regulating insulin delivery.

Aqueous concentrated plain mixtures of dextran and concanavalin A (con A) were examined for their rheological response to glucose for comparison with previously studied partially photopolymerized acrylic derivatives. Non-destructive oscillatory tests were undertaken within the linear viscoelastic range to examine the relationship between the rheometry and the stoichiometry of the interactive materials and to examine rheological parameters as affected by molecular weight, component ratio, temperature and glucose concentrations between 0 and 1% w/w. These simple formulations were studied at 1 and 10 Hz at 0.5% strain at both 20 and 37°C. A second simplified rheological test was undertaken to demonstrate gel-sol reversibility and to produce a measure of equilibria created between these gels and glucose solutions with which they are in contact. This mimics the conditions in which the gel acts as a responsive gateway in the insulin delivery device. It proved that the gels equilibrate with glucose solutions, rather than indiscriminately removing glucose. This is important in terms of producing a delivery device that can respond in a reversible, glucose concentration-dependent manner. The method used for this is capable of relative values only but provides information not obtainable from conventional rheometry.