A closed-loop artificial pancreas based on model predictive control: Human-friendly identification and automatic meal disturbance rejection

Type 1 diabetes is characterized by a lack of insulin production by the pancreas, causing high blood glucose concentrations and requiring external insulin infusion to regulate blood glucose. Continuous glucose sensors can be coupled with continuous insulin infusion pumps to create a closed-loop artificial pancreas. A novel procedure of “human-friendly” identification testing using multisine inputs is developed to estimate suitable models for use in an artificial pancreas. A constrained model predictive control (MPC) strategy is developed to reduce risks of hypo- and hyperglycemia (low and high blood glucose concentration). Meal detection and meal size estimation algorithms are developed to improve meal glucose disturbance rejection when incoming meals are not announced. Closed-loop performance is evaluated through simulation studies of a type 1 diabetic individual, illustrating the ability of the MPC-based artificial pancreas control strategy to handle announced and unannounced meal disturbances.     

Use of an artificial endocrine pancreas in diabetic pregnancy.

Insulin demand of 12 pregnant diabetics has been investigated with an artificial endocrine pancreas. A rise in insulin requirement during pregnancy which can be attributed to the effort of reaching normoglycemia and to the effect of contrainsular hormones has also been observed by this objective method. Assessment of basal insulin demand during the night might be helpful in optimizing conventional therapy by using long-acting insulins for supplementing basal insulin need. According to our results, pregnancy complicated by diabetes can be foreseen as one of the main applications of a glucose-controlled insulin infusion system.     

Attempted suicide by insulin injection treated with artificial pancreas.

An elderly woman with longstanding insulin dependent diabetes tried to commit suicide by injecting 400 units of insulin subcutaneously (usual total daily dose 56 units). She was admitted to hospital within the hour and treated with the aid of an artificial pancreas. This avoided the usual difficulty of the physician having to cope with rapid and substantial fluctuations in blood glucose concentrations and 67 hours after the overdose insulin was reinstituted. Using an artificial pancreas in insulin overdose is an important advance in management and may avoid the need for surgical intervention such as excising the site of injection.     

The use of the artificial pancreas in uremic diabetic patients.

Maintenance hemodialysis and renal transplantation are increasingly used for treating diabetic patients with end-stage renal failure. The use of the artificial pancreas is able to prevent large blood glucose fluctuations in these patients with atherosclerosis, advanced retinopathy or neuropathy in which hyper- and hypoglycemia are potentially deleterious. For this purpose, we have developed and are utilizing an artificial pancreas easily utilizable without special training by the staff of a dialysis unit. This artificial pancreas uses a polarographic glucose electrode with a fast response time (45 to 90 seconds), a terminal display for operator communication, and a continuous digital and analogyl display for control of the running operation. There is also a printer to display in tabular and graphical form the values at any time during the operation. In this preliminary study, 7 patients have been studied: five under repetitive hemodialysis for four hours, 3 times a week; one treated by peritoneal dialysis for 12 hours, twice a week and one controlled during, and 48 hours after, renal transplantation. The macroscopic pancreas normalizes blood glucose under these circumstances, helps in a better understanding of blood glucose homeostasis in uremic patients under dialysis, leads to a more precise evaluation of insulin needs, may help to improve the nutritional status of the patients, and has an educational value for the patient and the medical staff.     

Bioengineering in development of the hybrid artificial pancreas

The hybrid artificial pancreas for treatment of diabetes consists of insulin-secreting pancreatic tissue which is surrounded by a membrane that protects the tissue from rejection by the immune system following implantation. In this paper, we review the alternative therapeutic approaches for diabetes under study and then discuss the technical requirements that must be met by a hybrid device useful to humans. Previous work on intravascular and extravascular immunoisolation devices is reviewed from the standpoint of these requirements, and three critical unresolved issues are discussed: biocompatibility, oxygen supply limitations, and prevention of immune rejection.     

Development of human pancreas

The developmental sequence of human pancreatic secretory proteins has not previously been studied in detail. We applied immunohistochemistry to study 20 fetal and neonatal pancreas' (8th to 39th gestational weeks) using antisera against the following pancreatic secretory proteins: pancreatic secretory trypsin inhibitor (PSTI), serine proteinases (trypsin, chymotrypsin, and elastase I), and amylase. PSTI was first detected in developing buds of the pancreas during the 8th gestational week, and proteinases were observed in acinar cells during the 14th week of gestation. Immunoreactivity for both PSTI and proteinases was found in most acinar cells soon after their appearance. Immunoreactivity for amylase could not be detected in fetal or neonatal pancreas tissue. PSTI was also found in developing islets during the 14th gestational week, but the number of immunoreactive cells had decreased by term. Cells positive for serine proteinases were occasionally in contact with islets in second-trimester fetuses. In discussing these results, we give particular attention to the nonparallel appearance of secretory products in the fetal pancreas, and the significance of cells immunoreactive for secretory proteins in endocrine islets.     

Blood glucose monitoring and computer regulation by means of an artificial endocrine pancreas.

Extracorporeal blood glucose regulation has been implemented by a closed-loop system (artificial endocrine pancreas, "aep") of our own construct. Simple, highly flexible algorithms have been developed that allow smooth repair of a deranged glucose imbalance up to a period of 125 hours.     

Incorporation of sulfonylurea into N-isopropylacrylamide as an extracellular matrix for an artificial pancreas.

High-molecular-weight N-isopropylacrylamide copolymers with small amounts of sulfonylurea (SU, typically 2-4 mol% in the feed) were synthesized by free radical polymerization in benzene. SU-incorporated polymer solutions (5, 6, 8, and 10% w/v) in a culture medium (pH 7.4, 0.15 M ionic strength) with islet cells were mixed and poured into Millicells which supported gel formation. In order to increase the gelation temperature, the SU-incorporated copolymer gel, p(NiPAAm-co-SU), was blended with the p(NiPAAm-co-AAc) polymer at a ratio of 4 to 96. Interaction between the islet cells and the synthetic matrix of SU-incorporated copolymer gel resulted in effective cell viability and such cell functions as insulin secretion. To verify the specific interaction between the SU (K+ channel closer)-incorporated copolymer and islet cells, the cells were pretreated with diazoxide, an agonist of the ATP-sensitive K+ channel (K+ channel opener), before interaction between the polymer and islet cells. This treatment suppressed the action of SU on the islet cells. The results from this study provide evidence that the SU-incorporated copolymer stimulated insulin secretion by specific interaction between SU moieties in the polymer and the islet cells.     

Development of a cold storage solution for pancreas preservation

Canine pancreas tissue slices were incubated at 5 degrees C for 24 hr in solutions containing different saccharides (raffinose, sucrose, mannitol, or glucose). At the end of incubation tissue water (TW expressed as kg H2O/kg dry wt) was determined as a measure of tissue edema. Tissue edema was greatest in slices stored in Eurocollins (EC) solution (TW = 4.96 +/- 0.14) which contains glucose for osmotic pressure. The degree of edema was decreased by saccharides in proportion to their molecular mass: mannitol (MW = 180, TW = 3.84 +/- 0.08), sucrose (MW = 348, TW = 3.54 +/- 0.08), and raffinose (MW = 594, TW = 3.30 +/- 0.07). Tissue edema was also greatest in slices incubated in solutions containing the smallest molecular mass anions: Cl- (TW = 4.02 +/- 0.16), gluconate (TW = 3.69 +/- 0.10), and lactobionate (TW = 3.28 +/- 0.13). Cold storage of the intact pancreas in EC solution for 24 hr did not induce as much edema as in slices (TW = 2.88 +/- 0.10). However, on isolated reperfusion at normothermia (37 degrees C) the pancreas became edematous (TW = 3.33 +/- 0.12). Storage of the pancreas in a lactobionate-raffinose solution did not induce edema after 90 min of normothermic reperfusion. The suppression of tissue edema in the pancreas may be essential to obtaining long-term preservation (24-72 hr) of this organ which is currently limited to about 6-8 hr in EC solution. The newly developed lactobionate-raffinose solution appears to control tissue edema in both tissue slices and the intact-flushed out organ.     

Application of an artificial endocrine pancreas in the management of the diabetic surgical patient.

Application of the artificial endocrine pancreas in 12 patients undergoing total duodenopancreatectomy and 3 diabetics in whom different operations were performed proved to be safe for the patients with respect to blood glucose control and prevention of ketosis. In the postoperative period, essentially normal blood glucose values were obtained despite high caloric parenteral nutrition.     

Dynamic study of the blood viscosity of insulin-dependent diabetics by means of an artificial pancreas.

The blood viscosity of 15 insulin-dependent, poorly controlled, diabetic subjects was determined by using a microviscosimeter at low shear rates, with cylindrical cuvettes of the Couette type. It was found that the blood viscosity of these diabetics was more elevated than that of control patients (p less than 0.001). In ten diabetics, the return to a strict metabolic control over a period of more than 24 h by means of an artificial pancreas resulted in a significant systematic lowering of blood viscosity. These results suggest that the metabolic control of diabetes influences blood viscosity, and they underline the importance of an artificial pancreas for the dynamic study of the factors affecting blood viscosity during the course of diabetes.     

Development of the pancreas in medaka

In the present work, pancreatic organogenesis has been studied in the medaka (Oryzias latipes), a teleost fish with several advantages as an experimental system in developmental biology. We demonstrated that the pancreas develops from three primordia budding from the dorsal and ventral faces of the gut epithelium. Such buds then fuse to form a single endocrine islet surrounded by exocrine tissue. Interestingly, the endocrine tissue forms only from the dorsal bud. We next analyzed a collection of medakas that had been hybridized with cDNAs derived from an anterior brain library. We found new clones expressed in the pancreatic region demonstrating that the medaka can be used to define new genes expressed in the pancreatic region that follow a specific spatial and temporal pattern of expression.     

Development of artificial vaccines against HIV using defined epitopes.

HIV may not follow the paradigm that has been used successfully for developing most viral vaccines, namely, that the best vaccine is the one that most closely mimics natural infection. This approach is based on the premise that natural infection leads to long-lasting protective immunity, which may not be applicable to HIV. Also, some immune responses elicited by infection with HIV may enhance infection or contribute to the development of immune deficiency. To overcome these problems, an artificial vaccine could be constructed using only antigenic epitopes that elicit neutralizing antibodies, helper T cells, and CD8+ cytotoxic T cells, and avoiding epitopes that elicit deleterious responses. Progress has been made in identifying all three of these types of epitopes, in characterizing their activity in animals, and in demonstrating that at least two of these can be linked to induce neutralizing antibodies without a carrier. Methods have also been developed to induce cytotoxic T cells. It is therefore feasible to construct an artificial vaccine for HIV that should be safer and more effective than a natural whole viral or subunit vaccine.     

The external artificial pancreas: an instrument to induce remissions in severe recent juvenile diabetes. Comparison with a preprogrammed insulin infusion system.

Remission of juvenile insulin-dependent diabetes is a rare, temporary, and partial phenomenon which seems to be related to an improvement of the residual insulin secretion supported by prompt and rigorous insulin therapy. Thus, remissions allowing the replacement of insulin by oral drugs were attempted in 23 insulin dependent ketotic juvenile diabetics (age 10 +/- 2 years) of recent onset (apparent duration of diabetes 71 +/- 5 days) treated by an external artificial pancreas during 5 +/- 1 days and compared with 10 control diabetics treated by a less effective technique (preprogrammed insulin pump without feedback control) during 6 +/- 1 days. 18 (78%) remissions of long duration (1-26 months) occurred after artificial pancreas compared with 3 (30%) in the control group. Measurement of daily urinary C-peptide excretion confirmed the improvement of the residual insulin secretion in patients with insulin-induced remissions. Thus, the excellent blood glucose control given by an artificial pancreas seems necessary to lead to much more frequent remissions of diabetes than usually reported.     

Development in vitro of epithelial-cell monolayers derived from fetal rat pancreas.

Purified epithelial-cell monolayers were generated in vitro from explants of fetal rat pancreas. The extent of the development of the epithelial monolayer, as determined by planimetric analysis, was enhanced by the application of two methodological procedures: (a) preincubation of fetal pancreas in situ at 27 degrees C for 5 hr prior to dissection and explantation; and (b) incubation of the explants in medium containing a high concentration (50% to 70%) of fetal bovine serum. By utilizing such culture conditions, sheets of contiguous epithelial cells, with little or no peripheral fibroblastic contamination, were maintained for 9 days. Whereas the majority of cells within the monolayer had morphological characteristics of pancreatic ductal cells, endocrine cells were identified by the specific immunocytochemical localization of insulin and glucagon. In addition, insulin could be detected in the incubation medium throughout the course of experiment. The simplicity of this preparation offers some advantages over other techniques including reduced chance of contamination and reduced cellular damage or death. It provides a model for future studies directed toward developing individual cell strains derived from pancreatic epithelial cells.