This report takes an approach of laying the first steps to create an artificial pancreassystem as treatment for type 1 diabetes. This includes a thoroughly performedanalysis of the most intrusive physical factors, such as hormonal activity, time offset,errors of measurement and metabolism. Such factors raise a need forcompensation. A compensation that will enable the development of the link betweena continuous glugose monitoring(CGM)-device and an insulin infusion pump,a system that can be described as an Artificial Pancreas.Through analysis of measured glucose series, a mathematicalapproximation is presented to solve the time offset of CGM.The approximation gives sufficient results but with room for improvementFrom the analysis of affecting factors, a compensation model isdeveloped. The model is designed as a closed loop which is suitable for timecontinuous systems. The output of the compensation model equation presented here is adirective that would be read by an insulin pump.

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The effects of two types of cryopreservation, conventional freezing and vitrification, on the in vitro and in vivo function of a pancreatic substitute were investigated. Conventional freezing uses low concentrations of cryoprotective agents (CPAs), slow cooling and rapid warming and allows ice formation. Vitrification requires high concentrations of CPAs coupled with rapid cooling and warming to achieve a vitreous, or ice-free, state. A previously published mathematical model describing the mass transfer of CPAs through the alginate matrix of the substitute and the cell membrane was expanded to incorporate heat transfer as well as CPA cytotoxicity. Our results indicate that temperature of exposure is the most critical parameter for the proper design of CPA addition and removal protocols. The use of a mathematical model is critical to ensure CPA equilibration and minimize CPA exposure. Properly designed CPA addition and removal protocols were used for vitrification. The effects of cryopreservation on the biomaterial and the cellular function of a pancreatic substitute consisting of murine insulinomas encapsulated in calcium alginate/poly-L-lysine/alginate beads were assessed. In vitro results indicate that both vitrification and conventionally frozen perform comparably to fresh. However, in vivo studies reveal that vitrified beads perform worse than both conventionally frozen and fresh beads. With adjustments, it may be possible to improve the performance of the vitrified beads. Nevertheless, for this pancreatic substitute, conventional freezing is the better method and allows successful cryopreservation.

Type 1 diabetes is one of the most common chronic conditions in childhood and adolescence. Despite ongoing development of more physiological insulin preparations, recent advancements in insulin pump technology and more accurate blood glucose monitoring, in clinical practice it remains challenging to achieve normoglycaemia whilst reducing the risk of hypoglycaemia, particularly in young people with type 1 diabetes. Closed-loop insulin delivery (the artificial pancreas) is an emerging technology gradually progressing from bench to clinical practice. Closed-loop systems combine glucose sensing with computer-based algorithm informed insulin delivery to provide real-time glucose-responsive insulin administration. The key objective of my thesis is to evaluate the safety, efficacy and utility of closed-loop insulin delivery in children and adolescents with type 1 diabetes outside of the research facility setting. Results of five clinical trials are presented in the main chapters of this thesis. In a mechanistic study, the impact of glucose sensor operation duration on efficacy of overnight closed-loop was investigated comparing closed-loop performance on day 1 of sensor insertion to day 3 to 4 of sensor. Twelve adolescents with type 1 diabetes attended the research facility for two overnight visits. The sequence of the interventions was random. Despite differences in sensor accuracy, overnight CL glucose control informed by sensor glucose on day 1 or day 3-4 after sensor insertion was comparable. The model predictive controller appears to mitigate against sensor inaccuracies. In home settings, overnight closed-loop application was evaluated over three months in 25 children and adolescents with type 1 diabetes aged six to 18 years. The study was conducted at three centres in the UK and adopted a randomised cross-over design. Compared to sensor-augmented pump therapy, overnight home use of closed-loop increased the proportion of time sensor glucose was in target, and reduced mean glucose and hypoglycaemia. Two randomised crossover studies evaluated the safety and efficacy of day-and-night hybrid closed-loop insulin delivery in young people with type 1 diabetes aged 10 to 18 years over seven days, and 21 days, respectively. A total of 24 subjects were enrolled in this single centre trial. Free-living home use of day-and-night closed-loop in suboptimally controlled adolescents with type 1 diabetes was safe, and improved glucose control without increasing the risk of hypoglycaemia. Finally, closed-loop technology was assessed in five very young children (aged one to seven years) with type 1 diabetes in a two-period, crossover study. Closed-loop was used during both 3-week intervention periods, either with standard strength insulin (U100), or with diluted insulin (U20). The order of intervention was random. Free-living home use of day-and-night hybrid closed-loop in very young children with type 1 diabetes was feasible and safe. Glucose control was comparable during both intervention periods. Thus, use of diluted insulin during closed-loop insulin delivery might not be of additional benefit in this population. In conclusion, studies conducted as part of my thesis demonstrate that use of hybrid closed-loop insulin delivery systems in children and adolescents aged one to 18 years in free daily living without remote monitoring or supervision is feasible, safe and effective. My work supports the progression of this technology from research to mainstream clinical practice.

Diabetes is a growing chronic disease and a worldwide problem. Without any available cure in sight for the public other methods needs to be applied to increase the life quality of diabetic patients. Artificial Pancreas (AP), a concept of having a closed loop system to control the glucose level on Type 1 Diabetes (T1D) patients has been introduced and is under development. In this thesis, Model Predictive Control (MPC) has been re implemented from scratch in MATLAB/SIMULINK with associated Kalman filter and prediction function. It was implemented in the latest version of the UVA/Padova Simulator which is a tool approved by FDA for simulating diabetes treatment in order to speed up the AP development. Different MPC cost functions where tested together with integral action on a simplified system using a linear approximation of a population model. It was implemented and tuned with a new simulation tuning method using Genetic Algorithm (GA). It showed that the quadratic cost function without integral action was the best with respect to performance and time efficiency. 3 hours was the best prediction horizon and was used for the individualized tuning using the University of Virginia (UVA)/Padova simulator. For the individualized MPC, models identified by the University of Padova were used. These simulations showed that an individualized model could be used for improved T1D treatment compared to an average population model even though the results were mixed. Almost all of the patients got improved treatment with the closed treatment and non hypoglycemic event occurred. The identification of better models is a great challenge for the future development of the AP MPC due to the excitation problems.

For clinical translation of a pancreatic substitute, long-term storage is essential, and cryopreservation is a promising means to achieve this goal. The two main cryopreservation methods are conventional freezing and vitrification, or ice-free cryopreservation. However, as both methods have their potential drawbacks for cryopreservation of a pancreatic substitute, they must be systematically evaluated in order to determine the appropriate method of cryopreservation. Furthermore, previous studies have indicated benefits to encapsulation in 3-D adhesive environments for pancreatic substitutes and that adhesion affects cell response to cryopreservation. Thus, the overall goal of this thesis was to investigate cryopreservation effects on model pancreatic substitutes consisting of cells encapsulated in non-adhesive and adhesive 3-D alginate hydrogels. Murine insulinoma betaTC-tet cells encapsulated in unmodified alginate hydrogels were chosen as the model pancreatic substitute in a non-adhesive 3-D environment. Murine myoblast C2C12 cells, stably transfected to secrete insulin, encapsulated in partially oxidized, RGD-modified alginate hydrogels were chosen as the model pancreatic substitute in a 3-D adhesive environment. With respect to cryopreservation effects on intermediary metabolism of betaTC-tet cells encapsulated in unmodified alginate, results indicate that relative carbon flow through the tricarboxylic acid cycle pathways examined is unaffected by cryopreservation. Additionally, insulin secretory function is maintained in Frozen constructs. However, vitrification by a cryopreservation cocktail referred to as DPS causes impairment in insulin secretion from encapsulated betaTC-tet cells, possibly due to a defect in late-stage insulin secretion. Results from Stable C2C12 cells encapsulated in RGD vs. RGE-alginate indicate that up to one day post-warming, cell-matrix interactions do not affect cellular response to cryopreservation after vitrification or freezing. Although there are differences in metabolic activity and insulin secretion immediately post-warming for DPS-vitrified RGD-encapsulated Stable C2C12 cells relative to Fresh controls, metabolic activity and insulin secretion are maintained at all time points assayed for Frozen constructs. Overall, due to results comparable to Fresh controls and simplicity of procedure, conventional freezing is appropriate for cryopreservation of betaTC-tet cells encapsulated in unmodified alginate or Stable C2C12 cells encapsulated in partially oxidized, RGD-modified alginate.

abstract: A medical control system, a real-time controller, uses a predictive model of human physiology for estimation and controlling of drug concentration in the human body. Artificial Pancreas (AP) is an example of the control system which regulates blood glucose in T1D patients. The predictive model in the control system such as Bergman Minimal Model (BMM) is based on physiological modeling technique which separates the body into the number of anatomical compartments and each compartment's effect on body system is determined by their physiological parameters. These models are less accurate due to unaccounted physiological factors effecting target values. Estimation of a large number of physiological parameters through optimization algorithm is computationally expensive and stuck in local minima. This work evaluates a machine learning(ML) framework which has an ML model guided through physiological models. A support vector regression model guided through modified BMM is implemented for estimation of blood glucose levels. Physical activity and Endogenous glucose production are key factors that contribute in the increased hypoglycemia events thus, this work modifies Bergman Minimal Model ( Bergman et al. 1981) for more accurate estimation of blood glucose levels. Results show that the SVR outperformed BMM by 0.164 average RMSE for 7 different patients in the free-living scenario. This computationally inexpensive data driven model can potentially learn parameters more accurately with time. In conclusion, advised prediction model is promising in modeling the physiology elements in living systems. / Dissertation/Thesis / Masters Thesis Computer Science 2017

[EN] Type 1 diabetes mellitus is a chronic and incurable disease that affects millions of people all around the world. Its main characteristic is the destruction (totally or partially) of the beta cells of the pancreas. These cells are in charge of producing insulin, main hormone implied in the control of blood glucose. Keeping high levels of blood glucose for a long time has negative health effects, causing different kinds of complications. For that reason patients with type 1 diabetes mellitus need to receive insulin in an exogenous way. Since 1921 when insulin was first isolated to be used in humans and first glucose monitoring techniques were developed, many advances have been done in clinical treatment with insulin. Currently 2 main research lines focused on improving the quality of life of diabetic patients are opened. The first one is concentrated on the research of stem cells to replace damaged beta cells and the second one has a more technological orientation. This second line focuses on the development of new insulin analogs to allow emulating with higher fidelity the endogenous pancreas secretion, the development of new noninvasive continuous glucose monitoring systems and insulin pumps capable of administering different insulin profiles and the use of decision-support tools and telemedicine. The most important challenge the scientific community has to overcome is the development of an artificial pancreas, that is, to develop algorithms that allow an automatic control of blood glucose. The main difficulty avoiding a tight glucose control is the high variability found in glucose metabolism. This fact is especially important during meal compensation. This variability, together with the delay in subcutaneous insulin absorption and action causes controller overcorrection that leads to late hypoglycemia (the most important acute complication of insulin treatment). The proposals of this work pay special attention to overcome these difficulties. In that way interval models are used to represent the patient physiology and to be able to take into account parametric uncertainty. This type of strategy has been used in both the open loop proposal for insulin dosage and the closed loop algorithm. Moreover the idea behind the design of this last proposal is to avoid controller overcorrection to minimize hypoglycemia while adding robustness against glucose sensor failures and over/under- estimation of meal carbohydrates. The algorithms proposed have been validated both in simulation and in clinical trials. / [ES] La diabetes mellitus tipo 1 es una enfermedad crónica e incurable que afecta a millones de personas en todo el mundo. Se caracteriza por una destrucción total o parcial de las células beta del páncreas. Estas células son las encargadas de producir la insulina, hormona principal en el control de glucosa en sangre. Valores altos de glucosa en la sangre mantenidos en el tiempo afectan negativamente a la salud, provocando complicaciones de diversa índole. Es por eso que los pacientes con diabetes mellitus tipo 1 necesitan recibir insulina de forma exógena. Desde que se consiguiera en 1921 aislar la insulina para poder utilizarla en clínica humana, y se empezaran a desarrollar las primeras técnicas de monitorización de glucemia, se han producido grandes avances en el tratamiento con insulina. Actualmente, las líneas de investigación que se están siguiendo en relación a la mejora de la calidad de vida de los pacientes diabéticos, tienen fundamentalmente 2 vertientes: una primera que se centra en la investigación en células madre para la reposición de las células beta y una segunda vertiente de carácter más tecnológico. Dentro de esta segunda vertiente, están abiertas varias líneas de investigación, entre las que se encuentran el desarrollo de nuevos análogos de insulina que permitan emular más fielmente la secreción endógena del páncreas, el desarrollo de monitores continuos de glucosa no invasivos, bombas de insulina capaces de administrar distintos perfiles de insulina y la inclusión de sistemas de ayuda a la decisión y telemedicina. El mayor reto al que se enfrentan los investigadores es el de conseguir desarrollar un páncreas artificial, es decir, desarrollar algoritmos que permitan disponer de un control automático de la glucosa. La principal barrera que se encuentra para conseguir un control riguroso de la glucosa es la alta variabilidad que presenta su metabolismo. Esto es especialmente significativo durante la compensación de las comidas. Esta variabilidad junto con el retraso en la absorción y actuación de la insulina administrada de forma subcutánea favorece la aparición de hipoglucemias tardías (complicación aguda más importante del tratamiento con insulina) a consecuencia de la sobreactuación del controlador. Las propuestas presentadas en este trabajo hacen especial hincapié en sobrellevar estas dificultades. Así, se utilizan modelos intervalares para representar la fisiología del paciente, y poder tener en cuenta la incertidumbre en sus parámetros. Este tipo de estrategia se ha utilizado tanto en la propuesta de dosificación automática en lazo abierto como en el algoritmo en lazo cerrado. Además la principal idea de diseño de esta última propuesta es evitar la sobreactuación del controlador evitando hipoglucemias y añadiendo robustez ante fallos en el sensor de glucosa y en la estimación de las comidas. Los algoritmos propuestos han sido validados en simulación y en clínica. / [CAT] La diabetis mellitus tipus 1 és una malaltia crònica i incurable que afecta milions de persones en tot el món. Es caracteritza per una destrucció total o parcial de les cèl.lules beta del pàncrees. Aquestes cèl.lules són les encarregades de produir la insulina, hormona principal en el control de glucosa en sang. Valors alts de glucosa en la sang mantinguts en el temps afecten negativament la salut, provocant complicacions de diversa índole. És per això que els pacients amb diabetis mellitus tipus 1 necessiten rebre insulina de forma exògena. Des que s'aconseguís en 1921 aïllar la insulina per a poder utilitzar-la en clínica humana, i es començaren a desenrotllar les primeres tècniques de monitorització de glucèmia, s'han produït grans avanços en el tractament amb insulina. Actualment, les línies d'investigació que s'estan seguint en relació a la millora de la qualitat de vida dels pacients diabètics, tenen fonamentalment 2 vessants: un primer que es centra en la investigació de cèl.lules mare per a la reposició de les cèl.lules beta i un segon vessant de caràcter més tecnològic. Dins d' aquest segon vessant, estan obertes diverses línies d'investigació, entre les que es troben el desenrotllament de nous anàlegs d'insulina que permeten emular més fidelment la secreció del pàncrees, el desenrotllament de monitors continus de glucosa no invasius, bombes d'insulina capaces d'administrar distints perfils d'insulina i la inclusió de sistemes d'ajuda a la decisió i telemedicina. El major repte al què s'enfronten els investigadors és el d'aconseguir desenrotllar un pàncrees artificial, és a dir, desenrotllar algoritmes que permeten disposar d'un control automàtic de la glucosa. La principal barrera que es troba per a aconseguir un control rigorós de la glucosa és l'alta variabilitat que presenta el seu metabolisme. Açò és especialment significatiu durant la compensació dels menjars. Aquesta variabilitat junt amb el retard en l'absorció i actuació de la insulina administrada de forma subcutània afavorix l'aparició d'hipoglucèmies tardanes (complicació aguda més important del tractament amb insulina) a conseqüència de la sobreactuació del controlador. Les propostes presentades en aquest treball fan especial insistència en suportar aquestes dificultats. Així, s'utilitzen models intervalares per a representar la fisiologia del pacient, i poder tindre en compte la incertesa en els seus paràmetres. Aquest tipus d'estratègia s'ha utilitzat tant en la proposta de dosificació automàtica en llaç obert com en l' algoritme en llaç tancat. A més, la principal idea de disseny d'aquesta última proposta és evitar la sobreactuació del controlador evitant hipoglucèmies i afegint robustesa. / Revert Tomás, A. (2015). Robust strategies for glucose control in type 1 diabetes [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/56001 / TESIS

The need to have mechanisms and Technologies for the control of blood glucose levels is essential for people who have diabetes of any type. This disease still has no cure and is one of the main risk factors for cardiovascular diseases, such as heart attack, stroke, renal complications etc. The number of diabetic people in the world and in Brazil is alarming, in addition, Brazilians occupy the fourth place in the world ranking according to the last survey of the year, 2015, made by the International Diabetes Federation (IDF). Several studies has been conducted in order to obtain the best glycemic control of people with diabetes, one of the current forms of control under investigation is the development of an artificial pancreas. Through the union of three systems: glucose monitoring system, control algorithm and actuator system through an insulin infusion pump, it is possible to obtain efficient results in glycemic control as they already have studies. This work consists of developing a prototype of a low-cost and low-power embedded control system, Hardware in Loop (HIL), based on Arduino nano microcontroller, which can control the blood glucose level of a model of a type 1 diabetes patient, considering some perturbations and noises, using the Kalman filter as estimator. The results obtained with the implementation of the controller are analyzed in order to obtain a better performance. / A necessidade de ter mecanismos e tecnologias para o controle dos níveis de glicose no sangue é essencial para pessoas que possuem diabetes de qualquer tipo, visto que esta é uma doença que ainda não possui cura e é um dos principais fatores de riscos para doenças cardiovasculares, como infarto, AVC, complicações renais e etc. O número de pessoas diabéticas no mundo e no Brasil é alarmante, além disso, tem-se que os brasileiros ocupam o quarto lugar no ranking mundial de acordo com o último levantamento no ano de 2015 feito pela International Diabetes Federation (IDF). Vários estudos têm sido realizados no intuito de obter o melhor controle da glicemia de pessoas com diabetes, uma das formas de controle que está sendo pesquisada atualmente é o desenvolvimento de um pâncreas artificial. Através da união de três sistemas, sendo estes: o de monitoramento da glicemia, o de algoritmo de controle e o de atuador através de bomba de infusão de insulina, é possível que sejam obtidos resultados eficientes no controle da glicemia como já têm mostrado alguns estudos. Este trabalho consiste em desenvolver um protótipo de um sistema de controle embarcado, Hardware in Loop (HIL), baseado no microcontrolador nano Arduino, de baixo custo e de baixo consumo de energia que possa controlar o nível de glicose no sangue de um modelo de um paciente com diabetes tipo 1, considerando algumas perturbações e ruídos, utilizando o filtro de Kalman como estimador. Os resultados obtidos com a implementação do controlador são analisados buscando a obtenção de um melhor desempenho. / São Cristóvão, SE

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